6-substituted-5,6,7,8-tetrahydro-3-hydrazino(substituted hydrazino)pyrido(4,3-c)pyridazines

ABSTRACT

THIS INVENTION PROVIDES AMINOPYRIDAZINE DERIVATIVES OF FORMULA I,   3-(R1-N(-R2)-),5,6-(-CH2-A-CH2-CH2-)-PYRIDAZINE(-R8)(-R9)   WHEREIN R1 IS AMINO, OR AN   -N=C(-R3)-R4   GROUP, WHEREIN EACH OF R3 AND R4 IS ALKYL OF 1 TO 4 CARBON ATOMS, OF R3 AND R4 TOGETHER WITH THE CARBON ATOM TO WHICH THEY ARE BOUND, FORM A CYCLOALKYLIDENE RADICAL OF 5 TO 12 CARBON ATOMS, R2 IS HYDROGEN OR METHYL, A IS A-(CH2)N-GROUP, WHEREIN N IS 0 OR AN INTEGER FROM 1 TO 7, OR AN &gt;N-CO-R5 GROUP, WHEREIN R5 IS ALKYL OR ALKENYL OF 1 TO 16 CARBON ATOMS, CYCLOALKYL OF 3 TO 8 CARBON ATOMS, 1-ADAMANTYL, OR A-(CH2)M-R6 GROUP, WHEREIN M IS 0 OR AN INTEGER FROM 1 TO 4, AND R6 IS PHENYL; PHENYL MONOSUBSTITUTED BY FLUORINE, CHLORINE, BROMINE, ALKYL OR ALKOXY OF 1 TO 4 CARBON ATOMS, ALKYLMERCAPTO OF 1 TO 4 CARBON ATOMS, OF PHENYL; PHENYL SUBSTITUTED BY TWO OR THREE SUBSTITUENTS OF THE GROUP CHLORINE, ALKYL OR ALKOXY OF 1 TO 4 CARBON ATOMS; DIPHENYLMETHYL, THE PHENYL RINGS OF WHICH MAY BE MONOSUBSTITUTED BY FLUORINE, CHLORINE, BROMINE, ALKYL OR ALKOXY OF 1 TO 4 CARBON ATOMS; OR NAPHTHYL, OR AN-OR7 GROUP, WHEREIN R7 IS ALKYL OR ALKENYL OF 1 TO 4 CARBON ATOMS, OR PHENYL, PHENYLALKYL OR PHENYLALKENYL WHICH MAY BE MONOSUTITUTED ON THE PHENYL RING BY CHLORINE, ALKYL OR ALKOXY OF 1 TO 4 CARBON ATOMS, AND IN WHICH THE ALKYLENE OR ALKENYLENE CHAIN IS OF 1 TO 4 CARBON ATOMS, AND R8 AND R9 ARE EACH HYDROGEN OR ALKYL OF 1 TO 4 CARBON ATOMS, AND ACID ADDITION SALTS THEREOF, THE INVENTION ALSO PROVIDES PROCESSES FOR THE PRODUCTION OF SAID COMPOUNDS. SAID COMPOUNDS AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF ARE USEFUL AS ANTIHYPERTENSIVE AGENTS.

United States Patent 63 Claims ABSCT OF THE DISCLOSURE This invention provides aminopyridazine derivatives of formula 1,

A ITFR wherein R is amino, or an group, wherein each of R and R is alkyl of 1 to 4 carbon atoms, or R and R together with the carbon atom to which they are bound, form a cycloalkylidene radical of 5 to 12 carbon atoms, R is hydrogen or methyl, A is a (CH group, wherein n is 0 or an integer from 1 to 7, or an NCOR group, wherein R is alkyl or alkenyl of 1 to 16 carbon atoms,

cycloalkyl of 3 to 8 carbon atoms, l-adamantyl, or a (CH R group, wherein m is O or an integer from 1 to 4, and R is phenyl; phenyl monosubstituted by fluorine, chlorine, bromine, alkyl or alkoxy of 1 to 4 carbon atoms, alkylmercapto of 1 to 4 carbon atoms, or phenyl; phenyl substituted by two or three substituents of the group chlorine, alkyl or alkoxy of 1 to 4 carbon atoms; diphenylmethyl, the phenyl rings of which may be monosubstituted by fluorine, chlorine, bromine, alkyl or alkoxy of 1 to 4 carbon atoms; or naphthyl, or an OR group, wherein R is alkyl or alkenyl of 1 to 4 carbon atoms, or phenyl, phenylalkyl or phenylalkenyl which may be monosubstituted on the phenyl ring by chlorine, alkyl or alkoxy of 1 to 4 carbon atoms, and in which the alkylene or alkenylene chain is of 1 to 4 carbon atoms, and R and R are each hydrogen or alkyl of 1 to 4 carbon atoms, and acid addition salts thereof,

The invention also provides processes for the produc tion of said compounds.

Said compounds and pharmaceutically acceptable acid addition salts thereof are useful as antihypertensive agents.

This invention relates to aminopyridazine derivatives. In accordance with the invention there are provided new compounds of formula I,

R K N wherein R is amino, or an R3 -N=O/ group, wherein each of R and R is alkyl of 1 to 4 carbon atoms, or R and R together with the carbon atom to which they are bound, form a cycloalkylidene radical of 5 to 12 carbon atoms, R is hydrogen or methyl, A is a -(CH group, wherein n is 0 or an integer from 1 to 7, or an NCOR group, wherein R is alkyl or alkenyl of 1 to 16 carbon atoms,

cycloalkyl of 3 to 8 carbon atoms, l-adamantyl, or a (CH -R group, wherein m is 0 or an integer from 1 t0 4, and R is phenyl; phenyl monosubstituted by fluorine, chlorine, bromine, alkyl or alkoxy of 1 to 4 carbon atoms, alkylmercapto of 1 to 4 carbon atoms, or phenyl; phenyl substituted by two or three substituents of the group chlorine, alkyl or alkoxy of 1 to 4 carbon atoms; diphenylmethyl, the phenyl rings of which may be monosubstituted by fluorine, chlorine, bromine, alkyl or alkoxy of 1 to 4 carbon atoms; or naphthyl, or an -ORq group, wherein R is alkyl or alkenyl of 1 to 4 carbon atoms, or phenyl, phenylalkyl or phenylalkenyl which may be monosubstituted on the phenyl ring by chlorine, alkyl or alkoxy of 1 to 4 carbon atoms, and in which the alkylene or alkenylene chain is of 1 to 4 carbon atoms, and R and R are each hydrogen or alkyl of 1 to 4 carbon atoms, and acid addition salts thereof.

Further, in accordance with the invention a compound of formula I or an acid addition salt thereof may be obtained by processes which comprise (a) Reacting a compound of formula IIa,

R R and A are as defined above, and X is chlorine, bromine, mercapto, or an SR group, wherein R is benzyl or alkyl of l to 4 carbon atoms,

IIa

wherein wherein R is as defined above,

to produce a compound of formula Ia,

wherein R R R and A are as defined above,

wherein R and R are as defined above,

to produce a compound of formula Ib,

wherein R R R R R and A are as defined above,

and, where an acid addition salt is required, converting the resulting compound of formula I into such salt.

When R is N-alkylidene, the alkyl radicals R and R therein are preferably methyl or ethyl groups. When R is N-cycloalkylidene, this preferably contains 5 or 6 carbon atoms.

When A denotes an alkylene chain, this is preferably of 2 or 3 carbon atoms and is especially propylene.

When R and R are alkyl radicals, these especially signify methyl or tert.butyl.

When R is alkyl or alkenyl, the alkyl radicals preferably contain 1 to 7, especially 2 to 4 carbon atoms, and the alkenyl radicals preferably contain 3 to 6, especially 3 carbon atoms. When R is cycloalkyl, it is preferably of 4 to 6 carbon atoms.

When R is phenylalkyl, the alkylene chain thereof preferably contains 1 to 3, especially 1 carbon atom. R preferably, however, is an OR radical, or a phenylor diphenyl radical which may be substituted and is especially a phenyl radical which may be substituted. When a phenyl group in the substituent R is substituted by an alkyl or alkoxy radical, these radicals preferably contain 1 or 2 carbon atoms.

When R is an alkyl or alkenyl radical, this preferably contains 2 or 3 carbon atoms. When R is phenylalkyl, the alkylene chain thereof preferably contains 1 to 3 carbon atoms. When a phenyl ring in the substituent R is substituted by an alkyl or alkoxy radical, these radicals preferably contain 1 or 2 carbon atoms.

Process variant (a) is preferably effected by reacting a compound of formula IIa either with an excess of a compound of formula III, e.g. 5 to 10 mols of a compound of formula III per mol of a compound of formula IIa, or in the presence of another basic agent capable of binding an acid which may result during the reaction, e.g. a tertiary amine, or an alkali metal or alkaline earth metal hydroxide or carbonate. The reaction may be effected in the presence of an inert, preferably polar, organic solvent, e.g. a lower alcohol such as methanol, ethanol or isopropanol, or an open chain or cyclic ether such as dioxane, diethylene glycol dimethyl ether or tetrahydrofuran. An excess of a compound of formula III may also be used as solvent.

When a compound of formula IIb,

Rn Bi K T A\/\/ XI [lb wherein R R and A are defined above, and X is chlorine, bromine or mercapto,

is used, the reaction may, for example, be effected by heating a compound of formula 11b in hydrazine hydrate or methylhydrazine, optionally with the addition of one of the solvents and/or basic condensation agents indicated above, at normal pressure, at a temperature from approximately 20 to approximately 150 C., preferably at a temperature from to C., or at the boiling temperature of the reaction mixture, and under such conditions the reaction time is from 1 to 20 hours.

When a compound of formula IIc,

wherein R R R and A are as defined above,

is used, the reaction is preferably effected with an excess of hydrazine hydrate or methylhydrazine, optionally with the addition of one of the solvents and/ or basic condensation agents indicated above, in an autoclave, at a temperature from 80 to C.

Process variant (b) is preferably effected in the presence of an inert, preferably polar organic solvent, e.g. a lower alcohol such as methanol, ethanol or isopropanol, or an open chain or cyclic ether, e.g. diethylene glycol dimethyl ether, tetrahydrofuran or dioxane. Suitable reaction temperatures are from approximately 0 C. to the boiling temperature. Reaction times under preferred conditions are about 5 minutes to 20 hours. The product may be isolated by evaporating the reaction mixture to dryness, or allowing the crude product to crystallize as such or after extensive concentration of the solution.

The resulting compounds of formula I may be isolated from the reaction mixture and purified in accordance with known methods; the free bases may be converted into acid addition salts, and acid addition salts into free bases in conventional manner.

The starting materials may be obtained as follows:

(i) A compound of formula IId,

N f is Rs M IId wherein may be obtained by heating a compound of formula He,

wherein A R and R are as defined above,

with a suitable chlorinating or brominating agent, e.g. phosphorus oxychloride, phosphorus trior pentachloride, or phosphorus oxybromide, preferably to a temperature up to approximately 100 C. or to the boiling temperature of the reaction mixture.

(ii) A compound of formula IIf,

III

wherein R R and R are as defined above, and X is chlorine,

bromine, hydroXy or mercapto,

may be obtained by reacting a compound of formula Hg,

N t N R i HW HI IIg wherein R R and X are as defined above,

with a compound of formula V,

R CO-Cl V wherein R is as defined above,

in an inert solvent, e.g. a chlorinated hydrocarbon such as chloroform or ethylene chloride, in the presence of an acid-binding agent, e.g. an alkali metal carbonate or a tertiary amine such as triethyl amine, and where X is hydroxy or mercapto, the phenol or thiophenol ester resulting as by-product is saponified under weakly alkaline or acid conditions.

(iii) A compound of formula 11h,

N Rs wherein R and R are as defined above, and A denotes A or imino,

may, for example, be obtained by reacting a compound of formula IIi,

wherein R R A and X are as defined above,

with thiourea or, if desired, with sodium sulphide. The reaction is preferably effected in a polar organic solvent, e.g. a lower alcohol such as ethanol or dimethyl formamide, at a temperature from approximately 30 to approximately 100 C. Suitable reaction times are approximately /2 to 4 hours.

(iv) A compound of formula He may, for example, be obtained by reacting a compound of formula IIj,

wherein R and X are as defined above,

in the presence of an acid-binding agent, e.g. an alkaline earth carbonate or an alkali carbonate or hydroxide, e.g. potassium carbonate. The reaction is preferably effected in a polar organic solvent having a good dissolving power for the compound of formula IIj, e.g. in dimethll formamide.

6 (v) A compound of formula IIk,

r N R I 1 wherein R and R are as defined above,

may, for example, be produced by splitting off the R OCO group in a compound of formula III,

III wherein R R and R are as defined above,

with an acid, e.g. by heating for several hours in an acid medium, e.g. in hydrochloric acid, or with an alkali, e.g. by heating with an alkali metal hydroxide such as potassium hydroxide in a higher boiling alkanol such as nbutanol.

(vi) A compound of formula IIm,

IIm

wherein R and R are as defined above, and

A is a (CH,;),,-- group, wherein n is as defined above, or an NCORr, group, wherein R is as defined above,

may, for example, be obtained by cyclizing a compound of formula VII,

n p R A3 0112-00 OAlk VII wherein A R and R are as defined above, and Alk is alkyl of 1 to 4 carbon atoms,

in an inert solvent, e.g. a lower alcohol such as ethanol, in the presence of at least an equivalent amount of glacial acetic acid, with hydrazine hydrate or a salt of hydrazine. Suitable reaction temperatures are from to C., preferably the boiling temperature of the reaction mixture. The reaction may conveniently be effected under an inert gas atmosphere.

The resulting compound of formula VIII,

VIII

wherein A R and R are as defined above,

is oxidized, preferably with bromine, using a halogenated hydrocarbon such as chloroform or ethylene chloride as solvent.

A compound of formula VII may be obtained by reacting a compound of formula IX,

wherein A R and R are as defined above,

with a secondary amine, preferably a cyclic amine such as pyrrolidine, morpholine or piperidine, preferably in an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, if desired with the addition of a catalyst, e.g. p-toluenesulphonic acid or a molecular sieve, at an elevated temperature, preferably at the boiling temperature of the reaction mixture, to obtain an enamine of formula X,

A R and R are as defined above, and Y is a secondary amino group,

wherein and adding to this enamine, at room temperature, a bromoacetic acid alkyl ester in the presence of an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene, a hydrocarbon halide such as chloroform, or an ether, or dimethyl formamide, heating the reaction mixture for several hours, preferably to the boil, and again splitting the enamine group in the resulting reaction product of formula XI,

Alk is alkyl of 1 to 4 carbon atoms,

by heating with water, if desired with the addition of a dilute lye, ammonia solution or dilute mineral acid.

Insofar as the production of the starting materials is not particularly described, these are known or may be produced in accordance with known processes, or in a manner analogous to the processes described herein or to known processes.

The compounds of formula I are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as antihypertensive agents as indicated by tests in the hypertonic Grollman rat [method in accordance with A. Grollman, Proc. Soc. Exp. Biol. Med., 57, 104 (1944)] on administration of 0.1 to 10 mg./ kg. animal body weight of the compound.

For the above-mentioned use, the dosage administered will, of course, vary depending upon the compound employed, mode of administration and treatment desired. However, in general, satisfactory results are obtained when administered at a daily dosage of from about 0.1 to 10 mg./kg. animal body weight, preferably given in divided doses 2 to 4 times a day, or in sustained release form. For the larger mammals, the total daily dosage is in the range of from about 5 to 700 mg., and dosage forms suitable for oral administration comprise from about 1.3 to 350 mg. of the compound admixed with a solid or liquid carrier or diluent.

Particularly interesting compounds are 6-benzoyl-3-hydrazino-S,6,7,8 tetrahydropyrido[4,3-c]pyridazine and the corresponding isopropylidene hydrazone derivative, 3-hydrazino-5,6,7,8 tetrahydro 6 pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and the corresponding isopropylidene and Z-butyIidene-hydrazone derivatives, and 3 hydrazino 5,6,7,8,9,l-hexahydrocycloocta[c] pyridazine and the corresponding isopropylidenehydrazone derivative.

The above compounds, when administered in a capsule containing from about to 700 mg, produce the antihypertensive effect.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms possess the same order of activity as the free bases and are readily prepared in conventional manner. Suitable such salt forms include organic acid salts such as the fumarate, tartrate and benzenesulphonate, and mineral acid salts such as the hydrochloride, hydrobromide and sulphate.

The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule.

The invention also provides a method of treating hypertension in a warm-blooded animal, which comprises administering to an animal in need of such treatment a therapeutically effective dose of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof.

In the following non-limitative examples all temperatures are indicated in degrees centigrade.

EXAMPLE 1 3-hydrazino-5,6,7,8-tetrahydrocinnoline A mixture of 20.2 g. of 3-chloro-5,6,7,8-tetrahydrocinnoline and cc. of hydrazine hydrate in 50 cc. of absolute ethanol is heated at a bath temperature of for 17 /2 hours while stirring. After cooling the reaction mixture, this is almost completely concentrated, whereupon the title compound crystallizes as free base upon cooling with ice. M.P. 134-138 from dimethoxyethane/ether.

5.5 g. of the title compound are boiled in cc. of absolute ethanol with 7 g. of fumaric acid. After filtration and cooling of the reaction mixture, the yellow 3- hydrazino 5,6,7,8-tetrahydrocinnoline fumarate crystallizes. M.P. 159-161" (decomp.).

EXAMPLE 2 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta [c] pyridazine 11.7 g. of 3-chloro-5,6,7,8,9,l0-hexahydrocycloocta[c] pyridazine and 60 cc. of hydrazine hydrate are reacted in accordance with the process described in Example 1. The orange-coloured solution is completely concentrated, and the remaining crystalline crude title compound is washed with water. M.P. l45148 (decomp., from absolute ethanol).

EXAMPLE 3 5,6,7,8,9, l0-hexahydro-3-( l-methylhydrazino) cycloocta[c] pyridazine A suspension of 9.8 g. of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 50 cc. of methylhydrazine is stirred in an oil bath of 45 for 24 hours. The material dissolves completely during heating. After the reaction is complete, the mixture is evaporated to dryness, and the crude crystalline title compound is recrystallized twice from ether. The title compound has a M.P. of 78-79" (decomp.).

EXAMPLE 4 3-hydrazino-5,6,7,S-tetrahydro-6-methylcinnoline A suspension of 9.1 g. of 3-ch1oro-5,6,7,8-tetrahydro- 6-methylcinnoline in 100 cc. of hydrazine hydrate is vigorously stirred in an oil bath of 110 for 6 hours. The starting material melts upon heating and forms an oily pool. After cooling with ice, crude 3-hydrazino-5,6,7,8- tetrahydro-6-methylcinnoline precipitates. It is dissolved in chloroform, the solution is dried with sodium sulphate and concentrated in a Vacuum. 9 g. of the crude base are dissolved with 5.8 g. of fumaric acid in 50 cc. of methanol in a water bath. After cooling with ice, the bis (3-hydrazino-5,6 ,7,8-tetrahydro 6 methylcinnoline)trisfumarate, having a M.P. of 156-158 (decomp.), crystallizes.

The starting material may be produced as follows:

(a) A mixture of 112.1 g. of 4-methylcyclohexanone and 106.7 g. of pyrrolidine in 1.0- litre of benzene is heated to the boil at reflux for 2 hours, and the resulting water is continuously removed azeotropically. The mixture is concentrated, and the crude 4-methyl-l-pyrrolidinylcyclohexene(l) obtained as yellow oil is used in the next stage.

(b) A mixture of 171.2 g. of 4-methyl-1-pyrrolidinylcyclohexene(1) and 200.4 g. of bromoacetic acid ethyl ester in 1.5 litres of benzene is heated at reflux While stirring for 20 hours. 750 cc. of water are added to the mixture, and this is again heated to the boil at reflux for 3 hours, whereby 250 cc. of a 10% aqueous ammonia solution are added after one hour. The organic phase is separated, dried over sodium sulphate and concentrated in a vacuum. The crude 4-methylcyclohexanone-Z-acetic acid ethyl ester is used as such in the next stage.

(c) 200.1 g. of crude 4-methylcyclohexanone-Z-acetic acid ethyl ester and 50 g. of hydrazine hydrate are stirred at reflux in 600 cc. of absolute ethanol and 100 cc. of glacial acetic acid in a stream of nitrogen for 5 hours. The dark solution is completely concentrated in a vacuum and subsequently divided between chloroform and a aqueous caustic soda solution. After concentrating the organic phase in a vacuum, crude 2,3,4,4a,5,6,7,8-octahydro-6-methyl-3-cinnolinone is obtained as an oil, which crystallizes upon adding 1.2 litres of ether. 116118 from ethyl acetate.

(d) A mixture of 35.6 g. of bromine in 75 cc. of chloroform is added dropwise to a boiling solution of 39 g. of 2,3,4,4a,5,6,7,S-octahydro-6-methyl-3-cinnolinone in 200 cc. of chloroform Within one hour, and the mixture is stirred for a further hour at the same temperature. The hydrobromide of the reaction product, resulting after cooling with ice, is taken up in 150 cc. of a concentrated aqueous ammonia solution, and after a short time of action, insoluble 5,6,7,8-tetrahydro-3-hydroxy-6-methylcinnoline is filtered off. M.P. 193l95 (decomp., from acetonitrile) (e) 27.5 g. of 5, 6,7,8-tetrahydro-3-hydroxy-6-methylcinnoline are suspended in 120 cc. of phosphorus oxychloride, and the suspension is heated to the boil while stirring. The resulting solution is stirred for 1 hour at the boil and then concentrated to an oil in a vacuum. 150 cc. of ice/water and 40 cc. of concentrated ammonia solution are added to this oil, and the mixture is extracted twice with a total of 300 cc. of chloroform. The chloroform phase is concentrated in a vacuum, and 3-chloro- 5,6,7,S-tetrahydro-G-methylcinnoline is dissolved out of the resulting semicrystalline oil with n-hexane while heating. M.P. 6567 (decomp.).

EXAMPLE 5 3-hydrazino-6,7,8,9 tetrahydro (5H cyclohepta [c] pyridazine A suspension of 13.7 g. of 3-chloro-6,7,8,9 tetrahydro- (5H)cyclohepta [cJpyridazine in 100 cc. of hydrazine hydrate is stirred in an oil bath of 90 for 12 hours, whereby 30 cc. of dioxane are added after 2 /2 hours. The mixture is concentrated to a red oil, this is taken up in 300 cc. of chloroform, a small amount of a second layer is separated, and the chloroform solution is concentrated in a vacuum. The semicrystalline residue is immediately converted into the crystalline dihydrochloride of the title compound with hydrochloric acid in isopropanol. M.P. 225228 (decomp., from 95% ethanol).

The starting material may be produced as follows:

(a) 1-pyrrolidinylcycloheptene(1): Produced in a manner analogous to that described in Example 4(a) from 112.2. g. of cycloheptanone and 106.7 g. of pyrrolidine in 300 cc. of benzene and 2 g. of p-toluenesulphonic acid. Reaction time 96 hours. The oily crude product is used for the next reaction without purification.

(b) Cycloheptanone-2-acetic acid ethyl ester: Produced in a manner analogous to that described in Example 4(b) from 291.5 g. of crude 1-pyrrolidinylcycloheptene( 1) and 400.4 g. of bromoacetic acid ethyl ester. Reaction time 24 hours. The crude product is purified by distillation in a Water pump vacuum. B.P. 143-159 at 14 mm. of Hg.

(c) 2,3,4,4a, 6,7,8,9-octahydro(5H)cyclohepta[c]pyridazinone( 3): Produced in a manner analogous to that described in Example 4(e) from 49.5 g. of cycloheptanone- 2-acetic acid ethyl ester and 12.5 g. of hydrazine hydrate. Reaction time 4 hours. The yellow solution is concentrated in a vacuum, and the resulting oily crude product is crystallized from 200 cc. of ether. M.P. 108-109" from ethanol.

((1) 6,7,8,9 tetrahydro(5H) 3-hydroxycyclohepta [c]- pyridazine: Produced in a manner analogous to that described in Example 4(d) from 27.1 g. of 2,3,4,4a,6,7,8,9- octahydro(5H)cyclohepta[c]pyridazinone(3) and 26.1 g. of 1bromine. M.P. 200-203 (decomp., from 95% ethano (e) 3-chloro-6,7,8,9 tetrahydro (5'I-I)cyclohepta [c]pyridazine: Produced in a manner analogous to that described in Example 4(e) from 21.6 g. of '6,7,8,9-tetrahydro(5H)-3-hydroxycyclohepta[c]pyridazine and cc. of phosphorus oxychloride. M.P. 74-75 (decomp., from n-hexane).

EXAMPLE 6 6-tert.butyl-3-hydrazino-5,6,7,8-tetrahydrocinnoline A suspension of 13.8 g. of 6-tert.butyl-3-chloro-5,6',7,8- tetrahydrocinnoline in 100 cc. of hydrazine hydrate is stirred in an oil bath of 100 for 23 hours, whereby 20 cc. of tetrahydrofuran are added after 1 hour. The mixture is worked up as described in Example 4, and the resulting crude oily title compound is dissolved in 40 cc. of absolute ethanol, and hydrochloric acid in ethanol is added to the solution until an acid reaction is obtained. The hydrochloride which crystallizes is triturated with 100 cc. of concentrated ammonia, the insoluble title compound is filtered off and has a M.P. of 72-73 (decomp.).

The starting material may be produced as follows:

'(a) 4 tert.butyl 1-pyrrolidinyl-cyclohexene(1): Produced in a manner analogous to that described in Example 4(a) from 154.2 g. of 4-tert.butylcyclohexanone and 106.5 g. of pyrrolidine. The crude compound obtained as yellow oil is used for the next reaction without purification.

(b) 4-tert.butylcyclohexanone-Z-acetic acid ethyl ester: Produced in a manner analogous to that described in EX- ample 4(b) from 232 g. of crude 4-tert.butyl-1-pyrrolidinylcyclohexene( 1) and 200.4 g. of bromoacetic acid ethyl ester. The crude compound is used for the next reaction without purification.

(c) 4 tert.butyl-2,3,4,4a,5,6,7,8-octahydro-3-cinnolinone: Produced in a manner analogous to that described in Example 4(e) from 251.2 g. of crude 4-tert.butylcyclohexanone-Z-acetic acid ethyl ester and 50 g. of hydrazne hydrate. M.P. 16ll64 (decomp., from acetonitri e (d) 4 tert.butyl-5,6,7,8-tetrahydro-3-hydroxycinnoline: Produced in a manner analogous to that described in Example 4(d) from 31.7 g. of 4-tert.butyl-2,3,4,4a,5,6,7,8- octahydro-3-cinnolinone and 24 g. of bromine. Reaction tinlie 90 minutes. M.P. 220-223 (decomp., from acetonitri e).

(e) 6-tert-butyl-3-chloro 5,6,7,8 tetrahydrocinnoline: Produced in a manner analogous to that described in Example 4(e) from 14.1 g. of 4-tert-butyl-5,6,7,8-tetrahydro-3-hydroxycinnoline and cc. of phosphorus oxychloride. M.P. 96-97 (decomp., from n-hexane).

7 EXAMPLE 7 9.9 g. of 3-chloro-5,6,7,8,9,10,l1,12,13,14-decahydr'ocyclododeca[c]pyridazine and 200 cc. of hydrazine 'hydrate are heated in an autoclave in an oil bath of 130 for 16 /2 hours. The reaction solution is cooled with ice/ common salt, and the resulting crude product is boiled for a short time with 4 g. of fumaric acid in 150 cc. of isopropanol. The crystalline fumarate of the title compound is obtained upon cooling. M.P. 173-174" (decomp., from 95% ethanol).

The starting material may be produced as follows:

(a) 1-pyrrolidinylcyclododecene (1): Produced in a manner analogous to that described in Example 4(a) from 364 g. of cyclododecanone and 216 g. of pyrrolidine in 2.8 litres of benzene with the addition of 6 g. of ptouenesulphonic acid. Reaction time 24 hours at the boil. The reaction mixture is concentrated to a yellow oil, and the unchanged starting material is separated in a water pump vacuum. The resulting crude product is used for the next reaction without purification.

(b) Cyclododecanone-Z-acetic acid ethyl ester: Produced in a manner analogous to that described in Example 4(b) from 162.3 g. of crude l-pyrrolidinylcyclododecene (1) and 139 g. of bromoacetic acid ethyl ester. Reaction time 17 hours. The crude product is used for the next reaction without purification.

(c) 2,3,4,4a,5,6,7,8,9,10,11,12,13,14 tetradecahydrocyclododeca[c]pyridazinone (3): Produced in a manner analogous to that described in Example 4(c) from 205 g. of crude cyclododecanone-Z-acetic acid ethyl ester and 35 g. of hydrazine hydrate. The mixture is allowed to stand over night at room temperature, is cooled with ice, and the resulting crude product is used for the next reaction as such.

(d) 5,6,7,8,9,10,11,12,13,14 decahydro 3 hydroxycycloddeca[c]pyridazine: Produced in a manner analogous to that described in Example 4(d) from 60 g. of 2,3,4,4a,5,6,7,8,9,10,11,l2,l3,14 tetradecahydrocyclododeca[c]pyridazinone (3) and 40.6 g. of bromine. M.P. 188-189 (decomp., from isopropanol). The hydrobromide has a M.P. of 195-198 from ethanol/ether.

(e) 3-chloro-5,6,7,8,9,l0,11,12,13,14 decahydrocyclododeca[c]pyridazine: Produced in a manner analogous to that described in Example 4(c) from 26 g. of 5,6,7,8,9,10,11,12,13,14 decahydro 3 hydroxycyclododeca[c]pyridazine and 100 cc. of phosphorous oxychloride. M.P. 126128 (decomp., from isopropanol).

EXAMPLE 8 6-benzoyl-3-hydrazino-5,6,7,8- tetrahydropyridopyrido [4,3-c] pyridazine A suspension of 21.6 g. of 6-benzoyl-3-chloro-5,6,7,8- tetrahydropyrido[4,3-c]pyridazine in 80 cc. of hydrazine hydrate is boiled at reflux at an oil bath temperature of 110 for 1 hour. After a reaction time of approximately 15 minutes the material dissolves completely. The crude title compound resulting after cooling the mixture, is washed with a small amount of absolute ethanol and dissolved in 60 cc. of dimethyl formamide. 60 cc. of absolute ethanol are added to the solution, whereupon the title compound crystallizes. M.P. 220223 (decomp.).

The starting material may be produced as follows:

(a) l,2,3,6-tetrahydro 4 pyrrolidinylpyridine-1-car boxylic acid ethyl ester: Produced in a manner analogous to that described in Example 4(a) from 342.6 g. of 1- carbethoxy-4-piperidone and 214.0 g. of pyrrolidine. The product is purified by distillation in a high vaccum. B.P. 1l4150 at 0.03 mm. of Hg.

(b) 1-carbethoxy-4-piperidone-3-acetic acid ethyl ester: Produced in a manner analogous to that described in Example 4(b) from 1460 g. of l,2,3,6-tetrahydro-4-pyrrolidinylpyridine-l-carboxylic acid ethyl ester and 1250 g.

of bromoacetic acid ethyl ester. The crudeproduct is purified by vacuum distillation. B.P. 145170 at 0.05 mm. of Hg.

(c) 2,3,4,4a,5,6,7,8-octahydro 3 oXo-6-pyrido[4,3-c] pyridazinecarboxylic acid ethyl ester: Produced in a manner. analogous to that described in Example 4(c) from 514 g. of- 1-carbethoxy-4-piperidone-3-acetic acid ethyl ester and 100 g. of hydrazine hydrate. The crystalline crude product obtained after concentration of the mixture is recrystallized from 1 litre of ethanol. M.P. 163-l66 (decomp.).

(d) 6 carbethoxy-S,6,7,8-tetrahydro-3 (2H)pyrido[4,3- c]pyridazinone: Produced in a manner analogous to that described in Example 4(d) from 450.5 g. of 2,3,4,4a,5,6,- 7,8 octahydro-3-oxo-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 320 g. of bromine. l kgQof ice/water is added to the mixture, the chloroform portion is separated, and then acid aqueous phase is again extracted with 500 cc. of chloroform. The semicrystalline crude product obtained after concentrating the. chloroform phase, is recrystallized with 250 cc. of absolute ethanol. M.P. 165-168 (decomp.).

(e) A solution of 223.2 g. of 6-carbethoxy-5,6,7,8-tetrahydro-3(2H)pyrido[4,3-c]pyridazinone in 1 litre of concentrated hydrochloric acid is heated to the. boil atreflux for 22 hours while stirring. The mixture is concentrated in a vacuum, and the resulting crude crystalline hydrochloride of 5,6,7,8-tetrahydro-3(2H)pyrido[4,-3-c]pyridazinone, having a M.P. of 3073'l0 (decomp., from methanol), is suspended in 0.75 litres of methanol, and 0.4 litres of triethylamine are slowly added to the suspension. After stirring for 15 minutes and cooling the violet suspension, the crude base is obtained. 25 g. of the crude base are recrystallized from 300 cc. of methanol, mixed with 10 cc. of concentrated ammonia and 40 cc. of water, with the addition of a small amount of coal. 5,6,7,8-tetrahydro-3(2H)pyrido[4,3-c]pyridazinone has a M.P. of 223-225 (decomp.).

-'(f) 3 chloro 5,6,7,8 tetrahydropyrido[4,3 c] pyridazine: Produced in a manner analogous to that described in Example 4(c) from 30.3 g. of 5,6,7,8-tetrahydro-3(2H)pyrido[4,3 c]pyridazinone and 250 cc. of phosphorus oxychloride. The crude unstable base is converted into the maleate for working up. This is effected by boiling 24.8 g. of the base in 150 cc. of methanol with 17.5 g. of maleic acid. Upon cooling the solution, the crude maleate is obtained, which is recrystallized from methanol with the addition of a small amount of coal. 3-chloro-5,6,7,8-tetrahydropyrido[4,3 c]pyridazine maleate has a M.P. of 162164 (decomp.).

(g) A mixture of 12.6 g. of benzoyl chloride in cc. of ethylene chloride is added dropwise to a suspension of 25.6 g. of 3-chloro-5,6,7,8-tetrahydropyrido[4,3- c]pyridazine maleate in 250 cc. of ethylene chloride and 21.8 g. of triethylamine within 1 8 minutes at room temperature while stirring. The mixture is stirred at room temperature for a further 14 hours, 200 cc. of water are added, the organic phase is separated and concentrated to an oil in a vacuum. Upon adding ether/dimethoxyethane to this oil, crude 6 benzoyl 3 chloro 5,6,7,8- tetrahydropyrido[4,3-c]pyridazine is obtained. After recrystallization from absolute ethanol with the addition of a small amount of coal, the compound has a M.P. of -127 (decomp.).

EXAMPLE 9 3-hydrazino-5,6,7,8-tetrahydro-6 (0-toluoyl)pyrido- [4,3-c] pyridazine 13.0 g. of 3-chloro-5,6,7,8-tetrahydro 6 (o-toluoyl) pyrido[4,3-c]pyridazine and 100 cc. of hydrazine hydrate are reacted as described in Example 4. Reaction time 2 hours. The bis[3-hydrazino-5,6,7,8 tetrahydro 6 (0- toluoyl)pyrido[4,3-c]pyridazine]trisfumarate has a M.P. of 98-100 (decomp., from 95% ethanol).

EXAMPLE 10 6-benzoyl.-5,6,7,8-tetrahydro-3-( l-methylhydrazino) Py [4,3-c]pyridazine 13.7 g. of 6-benzoyl-3-chloro-5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine in 40 cc. of methyl hydrazine are stirred at a bath temperature of 50 for 6 /2 hours. The oil resulting after concentrating the reaction solution is dissolved in 200 cc. of chloroform, the solution is dried with sodium sulphate and again concentrated to an oil. This is boiled for a short time with 12.0. g. of gentisic acid in 100 cc. of methanol on a water bath. After concentrating the solution to approximately /3 of its volume, and cooling with ice, the bisgentisin-ate of the title compound precipitates. M.P. 166-168 (decomp., from absolute ethanol).

EXAMPLE 11 6-(o-chlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine 7.7 g. of 3-chloro-6-o-chlorobenzoyl) 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine and 30 cc. of hydrazine hydrate are stirred at a bath temperature of 80 for 20 hours with the addition of 25 cc. of isopropanol, and the mixture is worked up as described in Example 4. The light yellow foam, obtained after concentrating the chloroform phase, is dissolved in 50 cc. of 95 ethanol and boiled for a short time on a water bath with 5.8 g. of fumaric acid. The bis[6 (0 chlorobenzoyl) 3- hydrazino-5,6,7,8 tetrahydropyrido[4,3 clpyridazine] trisfum-arate has a M.P. of 144-l46 (decomp., from 95% ethanol).

The 3-chloro-6-(o-chlorobenzoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 28.5 g. of 3-chloro 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine maleate and 16.9 g. of o-chlorobenzoyl chloride. M.P. 97-99 (decomp., from 95% ethanol).

EXAMPLE 12 3-hydrazino-5,6,7,8-tetrahydro-6-(3-phenylpropionyl) Py [4,3-c]pyridazine '8.5 g. of 3-chloro-5,6,7,8-tetrahydro-6- (3-phenylpropionyl)pyrido[4,3-c]pyridazine and 80 cc. of hydrazine hydrate are stirred at a bath temperature of 80 for 4 hours. After cooling the reaction solution with ice, the title compound precipitates and is recrystallized from 95% ethanol. The title compound has a M.P. of 162- 165 (decomp.).

The 3-chloro-5,6,7,8-tetrahydro-6- 3-phenylpropionyl) pyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 28.6 g. of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 31.5 g. of 3- phenylpropionyl chloride. M.P. 134-137 from 95% ethanol.

EXAMPLE 13 6- (p-tert.butylbenzoyl)-3-hydrazino-5,6,7,8,-tetrahydropyrido [4,3-c] pyridazine 12.0 g. of 6-(p-tert.butylbenzoyl)-3 chloro 5,6,7,8- tetrahydropyrido[4,3-c]pyridazine and 75 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 4 hours. The crude crystalline base obtained after cooling the mixture with ice, is dissolved together with 7.2 g. of fumaric acid in 50 cc. of methanol, whereby 14 the bis[6-(p-tert.butylbenzoyl) 3 hydrazino 5,6,7,8- tetrahydropyrido[4,3 c1pyridazine]trisfumar-ate is obtained. M.P. l15-118 (decomp.).

The 6(p-tert.butylbenzoyl)-3 chloro 5,6,7,8 tetrahydropyrido[4,3-c]pyrid-azine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 34.2 g. of 3-chloro- 5,6,7,8 tetrahydropyrido[4,3 c]pyr'idazine maleate and 25' g. of tert.butylbenzoyl chloride. M.P. 157-160" (decomp., from 95 ethanol).

EXAMPLE 14 6- (3,3-diphenylpropionyl) -3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c] pyridazine 7.6 g. of 3-chloro-6-(3,3-diphenylpropionyl)-5, 6,7,8- tetrahydropyrido[4,3-c]pyridazine in 40 cc. of hydrazine hydrate and 40 cc. of dioxane are stirred at a bath temperature of 100 during 12 hours. The mixture is cooled with ice, whereupon the title compound precipitates and is recrystallized from ethanol/water (ratio 6: 1). The title compound has a M.P. of 208-211 (decomp.).

The 3 chloro-6-(3,3-diphenylpropionyl)-5,6,7,8-tetrahydropyrido[4,3-c1pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 14.3 g. of 3-chloro- 5,6,7,8 tetrahydropyrido[4,3-c] pyridazine maleate and 12.3 g. of [3,B-diphenylpropionic acid chloride. Reaction time 24 hours. The oily crude product is taken up in 100 cc. of absolute ethanol, whereupon it crystallizes. M.P. 175l78 (decomp., from methanol).

EXAMPLE 15 6-(3,4-dichlorobenzoyl)-3-hydrazino-5,6,7,S-tetrahydropyrido [4,3-c1pyridazine 10.2 g. of 3-chloro-6-(3,4-dichlorobenzoyl)-5, 6,7,8- tetrahydropyrido[4,3-c]pyridazine and 60 cc. of hydrazine hydrate are stirred at a bath temperature of for 24 hours. 50 cc. of isopropanol are subsequently added, and the mixture is heated for a further 2 hours. The crude title compound precipitates upon cooling the mixture in an ice/ methanol bath. It is triturated with 50 cc. of a 10% aqueous caustic soda solution, and the insoluble material is filtered off and recrystallized from ethanol. The title compound has a M.P. of 202-206 (decomp.).

The 3 chloro-6-(3,4-dichlorobenzoyl)-5,6,7,2-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8( g), from 3-chloro-5,6,7,8-tetrahydropyrido- [4,3-c1pyridazine maleate and 3,4-dichlorobenzoyl chloride. M.P. 188-191 (decomp., from dirnethyl formamide).

EXAMPLE 16 6-(2,6-dichlorobenzoyl)-3-hydrazino-5, 6,7,S-tetrahydropyrido [4,3-c] pyridazine 10.3 g. of 3 chloro-6-(2,6-dichlorobenzoyl)-5,6,7,8- tetrahydropyrido[4,3-c]pyridazine and 30 cc. of hydrazine hydrate are stirred at a bath temperature of for 24 hours with the addition of 40 cc. of dioxane, and the mixture is worked up as described in Example 13. The bis[6 (2,6 dichlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine]fumarate has a M.P. of 2092l1 (decomp., from absolute ethanol).

The 3 chloro-6-(2,6-dichlorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyradizine, required as starting material, may be produced from 3-chloro-5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine maleate and 2,6-dichlorobenzoyl chloride in a manner analogous to that described in Example 8(g). The oily crude product is taken up in absolute ethanol, whereby crystallization occurs. M.P. 181-184 (decomp., from acetonitrile).

1 EXAMPLE 17 6- (2,3-dimethylbenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine 10.3 g. of 3-chloro-6-(2,3-dimethylbenzoyl)-5,6,7,8- tetrahydropyrido[4,3-c]pyridazine and 50 cc. of hydrazine hydrate in 80 cc. of dioxane are heated in an oil bath of 80. After a reaction time of 60 hours, the mixture is concentrated in a vacuum, the oily residue is divided between 250 cc. of chloroform and 150 cc. of water, and after concentrating the chloroform phase, the resulting oily crude base is reacted with gentisic acid as described in Example 10. The gentisinate of the title compound has a M.P. of 176l79 (decomp.) after recrystallization from 150 cc. of methanol and 100 cc. of water.

The 3 chloro-6-(2,3-dimethylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 2,3-dimethylbenzoyl chloride. Reaction time 64 hours. M.P. 189-192" (decomp., from absolute ethanol).

EXAMPLE 18 3-hydrazino-5,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl pyrido [4,3-c] pyridazine 12.8 g. of 3-chloro-5,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl)pyrido[4,3-c]pyridazine and 40 cc. of hydrazine hydrate in 40 cc. of dioxane are stirred at a bath temperature of 100 for 4 /2 hours. The title compound has a M.P. of l94197 (decomp., from absolute ethanol/methanol 2:1).

The 3 chloro-S,6,7,8-tetrahydro-6-(3,4,5-trimethoxybenzoyl)pyrido[4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 3,4,5-trimethoxybenzoyl chloride. M.P. 165168 (decomp., from absolute ethanol).

EXAMPLE l9 3-hydrazino-5,6,7,8-tetrahydro-6-(4-phenylbutyryl) pyrido [4,3-c pyridazine 11.8 g. of 3-chloro-5,6,7,8-tetrahydro-6-(4-pheny1- butyryl)pyrido[4,3-c]pyridazine and 60 cc. of hydrazine hydrate are stirred at a bath temperature of 50 for 53 hours with the addition of 50 cc. of dioxane. The mixture is worked up as described in Example 10. The gentisinate of the title compound has a M.P. of 203205 (decomp., from methanol/ water 2: 1

The 3 chloro-5,6,7,8-tetrahydro-6-(4-phenylbutyryl) pyrido[4,3-c] pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and phenylbutyric acid chloride. M.P. 92-94 (decomp.).

EXAMPLE 20 3-hydrazino-5,6,7,8-tetrahydro-6- (p-toluoyl)pyrido- [4-,3-c] pyridazine 12.0 g. of 3-chloro-5,6,7,8-tetrahydro-6-(p-to1u0yl)- pyrido[4,3-c]pyridazine and 50 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 2 hours. The title compound has a M.P. of 207210 (decomp., from 95% ethanol).

The 3 chloro 5,6,7,8-tetrahydro-6-(p-toluoy1)pyrido [4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3- c]pyridazine maleate and p-toluoyl chloride. Reaction time 24 hours at room temperature. M.P. 152-153 (de- P? rom absolute ethanol)- 1 6 EXAMPLE 21 6- (m-chlorobenzoyl)-3-hydrazino-5,6,7,S-tctrahydropyrido [4,3 -c] pyrid azine 10.8 g. of 3-chloro-6-(m-chlorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 50 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 4 hours with the addition of 25 cc. of isopropanol, and the mixture is worked up to a crude base as described in Example 17, and this crude base is converted into the fumarate in a manner analogous to that described in Example 4. The fumarate of the title compound has a M.P. of 178- 180 (decomp., from absolute ethanol).

The 6 (m-chlorobenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, is obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3- c] pyridazine maleate and m-chlorobenzoyl chloride. M.P. 194197 (decomp., from methanol).

EXAMPLE 22 6-(p-bromobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine 10.2 g. of 6-(p-bromobenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 55 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 2 hours. The title compound has a M.P. of 192-195 (decomp., from absolute ethanol/methanol 3:1).

The 6 (p-bromobenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4, 3-c]pyridazine maleate and p-bromobenzoyl chloride. M.P. 164-167 (decomp., from absolute ethanol).

EXAMPLE 23 3-hydrazino-5,6,7,8-tetrahydro-6-(p-methoxybenzoyl) pyrido [4,3-c] pyridazine 10.5 g. of 3-chloro-5,6,7,8-tetrahydro-6-(p-methoxybenzoyl)pyrido [4,3-c]pyridazine and 100 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 1 hour. The title compound has a M.P. of 169172 (decomp., from 95 ethanol).

The 3 chloro-5,6,7,8-tetrahydro-6-(p-methoxybenzoyl) pyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4, 3-c]pyridazine maleate and p-methoxybenzoyl chloride. M.P. 163164 from 95% ethanol.

EXAMPLE 24 6-(o-fiuorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine 11.6 g. of 3-chloro-6-(o-fluorobenzoyl)-5,6,7,8-tetrahydropyrido [4,3-c]pyridazine and c.. of hydrazine hydrate are stirred at a bath temperature of 100 for 3 /2 hours. The title compound has a M.P. of 210213 (decomp., from ethanol/methanol 1:1).

The 3 chloro-6-(o-fiuorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-ch1oro-5,6,7,8-tetrahydropyrido [4,3-c]pyridazine maleate and o-fluorobenzoyl chloride. M.P. 144146 (decomp., from 95% ethanol).

EXAMPLE 25 3-hydrazino-5,6,7,8-tetrahydro-6-(o-methylphenacetyl) pyrido [4,3-c] pyridazine 10.0 g. of 3-ehloro-5,6,7,8-tetrahydro-6-(o-methylphenacetyl)pyrido[4,3-c]pyridazine and 35 cc. of hydrazine hydrate are stirred at a bath temperature of for 30 minutes. The title compound has a M.P. of -157 (decomp., from absolute ethanol).

1 7 The 3 chloro 5,6,7,8-tetrahydro-6-(o-methylphenacetyl)pyrido [4,3-c1pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,S-tetrahydropyrido [4,3-c]pyridazine maleate and o-methylphenacetyl chloride. M.P. 125-127 (decomp., from 95% ethanol).

EXAMPLE 26 6-(p-ethoxybenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido [4, 3-c] pyridazine 11.1 g. of 6-(p-ethoxybenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c1pyridazine and 60 cc. of hydrazine hy drate are stirred at a bath temperature of 100 for 1 hour and 40 minutes. The title compound has a M.P. of 171- 173 (decomp., from absolute ethanol).

The 6 (p-ethoxybenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,S-tetrahydropyrido [4,3-c]pyridazine maleate and p-ethoxybenzoyl chloride. M.P. 146149 (decomp, from 95% ethanol).

EXAMPLE 27 3-hydrazino-5,6,7, 8-tetrahydro-6 2-naphthoyl pyrido [4,3-c1pyridazine 8 g. of 3 chloro 5,6,7,8-tetrahydro-6-(Z-naphthoyl) pyrido[4,3-c]pyridazine and 60 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 2 hours. After approximately 1 hour and 30 minutes, a dissolution and reprecipitation is observed. After cooling With ice the solid material is filtered ofi and recrystallized from 200 cc. of methanoLThe title compound has a M.P. of 204- 207 (decomp.).

The 3 chloro-6-(2-naphthoyl)-5,6,7,8-tetrahydropyrido [4,3-c1pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,g-tetrahydropyrido[4,3- c]pyridazine maleate and Z-naphthoyl chloride. Reaction time 22 hours at room temperature. M.P. 167-170 (decomp., from 95% ethanol).

EXAMPLE 28 3-hydrazino-5,6,7,8-tetrahydro-6-pivaloylpyrido [4,3-c] pyridazine 11.4 g. of 3-chloro-5,6,7,8-tetrahydro-6-pivaloylpyrido [4,3-c]pyridazine,and 100 cc. of hydrazine hydrate are boiled at reflux at a bath temperature of 110 for 1% hours While stirring. The crude title compound is taken up in 100 cc. of chloroform, is dried with sodium sulphate, the chloroform solution is again concentrated, and recrystallized from 20 cc. of absolute ethanol. The title compound hasa M.P. of 158160 (decomp.).

The 3-chloro-5,6,7,8-tetrahydro-6-pivaloylpyrido[4,3-c] pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3 cJpyridazine maleate and pivalic acid chloride. Reaction time 24 hours at room temperature. M.P. 140142 (decomp., from ethanol).

EXAMPLE 29 3-Hydrazino-5,6,7,8-tetrahydro-6-myristinoylpyrido- [4,3-c] pyridazine 11.0 g. of 3-chloro-5,6,7,S-tetrahydro-6-myristinoylpyrido[4,3-c]pyridazine and 110 cc. of hydrazine hydrate are stirred at reflux at a bath temperature of 80 for 26 hours with the addition of cc. of tetrahydrofuran, and the mixture is Worked up as described in Example 28. The crystallinecrude base still contains a by-product, which may be separated by producing the hydrochloride. This is effected by dissolving the crude base in 100 cc. of hydrochloric acid in ethanol. After a short time the hydrochlorideof the title compound crystallizes. M.P. 210213 (decomp, from ethanol).

The 3 chloro 5,6,7,8 tetrahydro-6-myristinoylpyrido- [4,3-c]pyrida2ine, required as starting material, is produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and myristic acid chloride. M.P. 8687 from ethanol.

EXAMPLE 30 6-butyryl-3-hydrazino-5,6,7, 8-tetrahydropyrido [4,3-c] pyridazine 8.4 g. of 6-butyryl-3-chloro-5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine and 30 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 45 minutes, and the mixture is worked up as described in Example 4. The bis(6-butyryl-3-hydrazino 5,6,7,8 tetrahydropyrido[4,3- c]pyridazine)trisfumarate has a M.P. of 177-179 (decomp., from ethanol/methanol 5:2).

The 6-butyryl-3-chloro-5,6,7,8-tetrahydropyrido[4,3 c] pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3 chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and butyric acid chloride. Reaction time 27 hours. M.P. 130133 from acetonitrile.

EXAMPLE 3 1 3-hydrazino-6-octanoyl-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine 11.5 g. of 3-chloro-6-octanoyl-5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine, dissolved in 50 cc. of dioxane, and 30 cc. of hydrazine hydrate are stirred at a bath temperature of for 16 hours, and the mixture is Worked up as described in Example 17. The gentisinate of the title compound has a M.P. of 164-166 (decomp., from methanol).

EXAMPLE 32 3-hydrazino-5,6,7, 8-tetrahydro-6- (2-n-propylvaleroyl) pyrido [4,3-c] pyridazine 11.8 g. of 3-chloro-5,6,7,8-tetrahydro-6-(Z-n-propylvaleroyl)pyrido[4,3c]pyridazine and 40 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 20 hours. The crude base, having a M.P. of 123-126 (decomp.), is dissolved in methanol, and fumaric acid is added until the solution indicates a pH of 4, and boiling is effected for a short time. After cooling with ice the bis[3 hydrazino 5,6,7,8 tetrahydro 6 (2 n propylvaleroyl)pyrido [4,3-c] pyridazine] trisfumarate crystallizes. M.P. 96-100 (decomp.).

The 3-chloro-5,6,7,8-tetrahydro-6-(Z-n-propylvaleroyl) pyrido[4,3-c]pyridazine, required as starting material, is produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine maleate and 2-n-propylvaleroyl chloride. The organic phase is concentrated, and the crude product is extracted from the resulting solid residue with a Soxhlet extraction apparatus, and is recrystallized from cyclohexane. M.P. 9495.

EXAMPLE 33 3-hydrazino-6-hexahydrobenzoyl-5,6,7, 8-tetrahydropyrido- [4,3-c1pyridazine 8.6 g. of 3-chloro-6-hexahydrobenzoyl-5,6,7,S-tetrahydropyrido[4,3-c]pyridazine and 60 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 2 hours. The crystalline crude base obtained upon cooling the reaction solution, is recrystallized from acetonitrile with the addition of purifying charcoal, and is dissolved together with 4 g. of gentisic acid in 80 cc. of absolute ethanol Wth heating. The gentisinate of the title compound crystallizes upon cooling the solution. M.P. 188490 (decomp.).

The 3-chloro-6-hexahydrobenzoyl 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro 5,6,7,8 tetrahydropyrido [4,3-c1pyridazine maleate and cyclohexanecarboxylic acid 19 chloride. M.P. 144-146 (decomp., from absolute ethanol).

EXAMPLE 34 6-( l-adarnantonyl -3-hydrazino-5,6,7,8-tetrahydropyrido- [4,3-c1pyridazine 8.1 g. of 6-(l-adamantonyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 75 cc. of hydrazine hydrate in 150 cc. of dioxane are stirred at a bath temperature of 100 for 5 hours. The crude base is converted into bis['6-(l-adamantonyl)-3-hydrazino 5,6,7,8 tetrahydropyrido[4,3-c1pyridazine]trisfumarate with 2.8 g. of fumaric acid in a solvent mixture of 50 cc. of absolute ethanol and cc. of methanol. M.P. 140-142 (decomp.).

The 6-(1-adamantonyl)-3-chloro 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine maleate and l-adamantanecarboxylic acid chloride. M.P. 260-261 (decomp., from dimethyl formamide).

EXAMPLE 6-cyclobutanecarbonyl-3-hydrazino-5,6,7, 8-tetrahydropyrido [4,3-c] pyridazine 13.4 g. of 3-chloro-6-cyclobutyryl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 75 cc. of hydrazine hydrate are stirred at a bath temperature of 100 for 1 hour. The oil obtained after concentrating the mixture in a vacuum is divided between water and chloroform/ethanol 9: 1, and the organic phase is worked up as described in Example 10. The gentisinate of the title compound has a M.P. of 196-l98 (decomp., from 95% ethanol/methanol 1:1).

The 3 chloro-6-cyclobutyryl-5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3- c]pyridazine maleate and cyclobutane-carboxylic acid chloride. M.P. 104106 (decomp., from absolute ethanol).

EXAMPLE 36 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido [4,3-c] pyridazinecarboxylic acid ethyl ester 113 g. of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c] pyridazinecarboxylic acid ethyl ester and 470 cc. of hydrazine hydrate are stirred at reflux at a bath temperature of 110 for 1 hour. The title compound has a M.P. of 145147 (decomp., from absolute ethanol).

The 3-chloro 5,6,7,8 tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid ethyl ester, required as starting material, may be produced in a manner analogous to that described in Example 4(e), from 300 g. of 6-carbethoxy- 5,6,7,8-tetrahydro 3(2H)pyrido[4,3-c]pyridazinone and 850 cc. of phosphorus oxychloride. The crude product is recrystallized from 700 cc. of absolute ethanol. M.P. 102- 105 (decomp.).

EXAMPLE 37 5 ,6,7,8-tetrahydro-3-( l-methylhydrazino -6-pyrido [4,3-c] pyridazinecarboxylic acid ethyl ester 72.6 g. of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c] pyridazinecarboxylic acid ethyl ester are heated at reflux in 300 cc. of methylhydrazine at a bath temperature of 110 for 1 hour while stirring, and the mixture is concentrated, the residue divided between chloroform and water and after concentrating the chloroform phase the title compound is obtained, M.P. 121-123 (dec., from dimethoxyethane) EXAMPLE 38 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid methyl ester 16.5 g. of 3-chloro-S,6,7,S-tetrahydro-6-pyrido[4,3-c] pyridazinecarboxylic acid methyl ester and 70 cc. of hydrazine hydrate are heated in a water bath for 1 hour. The title compound has a M.P. of 178180 (decomp., from acetonitrile) The starting material may be produced as follows:

(a) A mixture of 226.2 g. of l-methylpiperidone and 1 litre of benzene is added dropwise to a mixture heated to 70 of 378 g. of chloroformic acid methyl ester and 2 litres of benzene within minutes while passing a stream of nitrogen through the mixture. The mixture is subsequently stirred while boiling at reflux for 4 /2 hours' After cooling the mixture with ice, at small amount of precipitated crystalline material is filtered with suction, and the filtrate is concentrated in a vacuum. The resulting oil is distilled in a water pump vacuum. 1-carbomethoxy-4-piperidone is obtained as main fraction at a B.P. of 128- 137 at 13 mm. of Hg.

(b) l,2,3,6-tetrahydro 4 pyrrolidinylpyridine 1- carboxylic acid methyl ester: Produced in a manner analogous to that described in Example 4(a), from 420 g. of 1-carbomethoxy-4-piperidone and 285 g. of pyrrolidine. The crude product is purified by vacuum distillation. B.P. 200 at 0.01 mm. of Hg.

(0) 1-carbomethoxy-4-piperidone-3-acetic acid methyl ester: Produced in a manner analogous to that described in Example 4(b), from 420.4 g. of 1,2,3,6-tetrahydro-4- pyrrolidinylpyridine-l-carboxylic acid methyl ester and 306 g. of bromoacetic acid methyl ester. Reaction time 18 hours. The crude product is purified by vacuum distillation. B.P. 220240 at 0.2 mm. of Hg.

(d) 2,3,4,4a,5,6,7,8 octahydro 3 oxo-6-pyrido[4,3- c]pyridazine carboxylic acid methyl ester: Produced in a manner analogous to that described in Example 4(e), from 45.8 g. of 1-carbomethoxy-4-piperidone-3-acetic acid methyl ester and 10 g. of hydrazine hydrate in 400 cc. of absolute methanol and 20 cc. of glacial acetic acid. M.P. 163-165 (decomp., from benzene).

(e) 6-carbomethoxy 5,6,7,8-tetrahydro-3 (2H) pyrido- [4,3-c]pyridazinone: Produced in a manner analogous to that described in Example 4(d), from 27.9 g. of 2,3,4,4a,- 5,6,7,8-octahydro 3 oxo-6-pyrido[4,3-c]pyridazinecarboxylic acid methyl ester and 21.1 g. of bromine. Reaction time 3 hours. After cooling, 100 cc. of ice/Water are added to the mixture, and the pH is adjusted to between 3 and 4 by the addition of 38 cc. of a 10% aqueous caustic soda solution. The organic phase is separate and concentrated in a vacuum to a semicrystalline crude product. After recrystallization from methanol the compound has a M.P. of 192195 (decomp.).

(f) 3-chloro 5,6,7,8 tetrahydro-tS-pyrido[4,3-c]pyridazinecarboxylic acid methyl ester: Produced in a manner analogous to that described in Example 4(e), from 4.7 g. of 6-carbomethoxy-5,6,7,8-tetrahydro-3(2H)pyrido- [4,3-c]pyridazinone and 20 cc. of phosphorus oxychloride. Purification by extraction with ligroin. M.P. 92-94 (decomp.).

EXAMPLE 39 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido [4,3-c] pyridazinecarboxylic acid benzyl ester 19.2 g. of crude oily 3 chloro-S,6,7,8-tetrahydro-6- pyrido[4,3-c]pyridazinecarboxylic acid benzyl ester and 100 cc. of hydrazine hydrate are stirred at a bath temperature of 70 for 7 /2 hours, and the mixture is worked up to the crude title compound in a manner analogous to that described in Example 37, and this compound is recrystallized from acetonitrile. M.P. 137 (decomp.).

The 3-chloro 5,6,7,8 tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid benzyl ester, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5.6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and chloroformic acid benzyl ester. The oily crude product is used as such for the next reaction.

21 EXAMPLE 4o 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c1pyridazinecarboxylic acid allyl ester 23.4 g. of crude oily 3-chloro-5,6,7,8-tetrahydro-6- pyrido[4,3-c]pyridazinecarboxylic acid allyl ester and 150 cc. of hydrazine hydrate are heated at a bath temperature of 100 for 4 hours while stirring with the addition of 50 cc. of dioxane. The yellow oil obtained after concentrating the mixture is taken up in chloroform and separated from the precipitated hydrazine hydrate. 20.6 g. of the crude base obtained after concentrating the chloroform phase, are dissolved with 15.4 g. of gentisic acid in 150 cc. of absolute ethanol whilst hot. The crude gentisinate of the title compound crystallizes upon cooling the solution, and after recrystallization from methanol has a M.P. of 171173 (decomp.).

The 3 chloro 5,6,7,8 tetrahydro-6-pyrido[4,3-c] pyridazinecarboxylic acid allyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and chloroformic acid allyl ester. The oily crude product is used for the next reaction without purification.

EXAMPLE 41 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c1pyridazinecarboxylic acid ethyl ester A mixture of 1.7 g. of 3-benzylmercapto-5,6,7,8-tetrahydro 6 .pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, 1.3 g. of hydrazine hydrate and 10 cc. of 95% ethanol is heated at a bath temperature of 150 in an autoclave for 16 hours. The crude oil obtained upon concentrating the reaction solution in a vacuum, is divided between 70 cc. of chloroform and 25 cc. of a 10% aqueous caustic soda solution. The organic phase is concentrated, and the resulting oil is chromatographed on 40 g. of silica gel. The title compound is eluted with chloroform/methanol 95:5. M.P. 145147 (decmp.).

The starting material may be obtained as follows:

(a) A solution of 12.1 g. of 3-chloro-5,6,7,8-tetrahy dro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 4.2 g.. of thiourea in 200 cc. of absolute ethanol is heated at reflux in an oil bath of 110 for two hours while stirring. The dark reaction solution is completely concentrated in a vacuum, and the resulting crude, semicrystalline ,6,7,8 tetrahydro+3-mercapto-6-pyrido [4,3-c] pyridazinecarboxylic acid ethyl. ester is crystallized from 200 cc. of 95% ethanol. M.P. 18l183 (decomp., from 95 ethanol).

(b) A mixture of 13.2 g. of benzyl bromide in 75 cc. of dimethyl formamide is added dropwise within 2 hours to a suspension heated to-50 of 18.5 g. of 5,6,7,8-tetrahydro 3 mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 12.8 g. of potassium carbonate in 200 cc. ofdimethyl formamide. The mixture is subsequently stirred at the'same'temperature for 20 hours and is then completely concentrated in a vacuum. The residue is divided between 200 cc. of chloroform and 50 cc. of water, the organic phase is separated and concentrated to a dark oil in a vacuum. This is chromatographed on an aluminium oxide column, and elution is effected with a mixture of benzene/petroleum ether 2:1. The crude oily 3 benzyl mercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c] pyridazinecarboxylic acid ethyl ester, obtained after concentrating the eluate, crystallizes from 75 cc. of ether after the addition of 25 cc. of petroleum ether. M.P. 6768 (decomp.).

EXAMPLE 42 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ether 3.8 g. of 3ethylmercapto-5,6,7,S-tetrahydro-S-pyrido- [4,3-c1pyridazine carboxylic acid .etheyl ester and 3.6 g. of hydrazine hydrate are reacted in accordance with the 22 process described in Example 41. The oily crude product is crystallized from ethanol/ether. The title compound has a M.P. of 144-146 (decomp., from ethanol).

The 3 ethylmercapto 5,6,7,8 tetrahydro-6-pyrido- [4,3-c1pyridazinecarboxylic acid ethyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 41(b), from 5,6,7,8-tetrahydro 3 mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and ethyl bromide. M.P. 5456 from ligroin.

EXAMPLE 43 5 ,6,7,8tetrahydro-3-( l-methylhydrazino -6-pyrido [4,3-c] pyridazinecarboxylic acid ethyl ester 4.8 g. of 5,6,7,8-tetrahydro-3-mercaptopyrido[4,3-c] pyridazinecarboxylic acid ethyl ester and 20 cc. of methyl hydrazine are stirred at a bath temperature of for 1 hour. The title compound has a M.P. of 121-123 (decomp., from dimethoxyethane).

EXAMPLE 44 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido [4,3 -c] pyridazine A solution of 2.7 g. of 6-benzoy1-5,6,7,8-tetrahydro-3- mercaptopyrido[4,3-c]pyridazine in 30 cc. of hydrazine hydrate is stirred at a bath temperature of for 15 minutes. After 5 minutes a beige coloured precipitate results. After gas evolution is complete, the mixture is cooled with ice and the precipitated title compound is filtered off. The title compound has a M.P. of 220223 (decomp., from absolute ethanol).

The 6 benzoyl 5,6,7,8-tetrahydro-3-mercaptopyrido- [4,3-c1pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 41(a), from 27.4 g. of 6-benzoyl-3-chloro-5,6,7,8- tetrahydropyrido[4,3-c1pyridazine and 8.4 g. of thiourea. After cooling the reaction mixture with ice, the compound precipitates. M.P. 225228 (decomp, from glacial acetic acid).

EXAMPLE 45 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido- [4,3-c] pyridazine A mixture of 3.3 g. of 3-ethylmercapto-6-benzoyl-5,6,7, S-tetrahydropyrido[4,3-c]pyridazine and 15 cc. of hydrazine hydrate in 15 cc. of absolute ethanol is heated in an autoclave at a bath temperature of 150 for 14 hours. A maximum pressure of 13 atmospheres results. The oil obtained after concentrating the reaction mixture in a vacuum, is divided between chloroform and water, and the organic phase is concentrated to a semicrystalline residue. After recrystallization from dimethyl formamide, the title compound, having a M.P. of 220223 (decomp.), is obtained.

The 3-ethylmercapto-6-benzoyl 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 41(b), from 34.8 g. of 6-benzoyl-3-mercapto- 5,6,7,8tetrahydropyrido[4,3-c]pyridazine and 16.8 g. of ethyl bromide. Reaction time 19 hours. Working up as described in Example 41(b), eluantzbenzene. M.P. 132- 135 (decomp, from isopropanol/ether).

EXAMPLE 46 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido- [4,3-c] pyridazine A solution of 4.0 g. of 3-benzylmercapto-6-benzoyl-5,6, 7,8-tetrahydropyrido[4,3-c]pyridazine and 1.5 g. of hydrazine hydrate in 10 cc. if 95 ethanol is heated in an autoclave at a bath temperature of for 16 hours. The oil obtained after concentrating the reaction mixture in a vacuum, is divided between chloroform and a small amount of water, and the organic phase is concentrated to a red oil. The title compound is obtained by crystallization from dimethyl formamide. M.P. 220223 (decomp.).

The fumarate of the title compound, having a M.P. of 188190 (decomp.), is obtained by reacting the title compound with the calculated amount of fumaric acid in a small amount of 95% ethanol.

The 3-benzylmercapto-6-benzoyl 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 41(b), from 6-benzoyl-3-mercapto 5,6,7,8- tetrahydropyrido[4,3-c]pyridazine and benzyl bromide. Purification by chromatography on aluminum oxide, eluantzbenzene. M.P. 114116 (decomp., from ether).

EXAMPLE 47 6-benzoyl-5,6,7,8-tetrahydro-3- l-methylhydrazino) pyrido [4,3 -c] pyridazine A solution of 3.4 g. of 6-benzoyl-5,6,7,8-tetrahydro-3- mercaptopyrido[4,3-c]pyridazine in 40 cc. of methylhydrazine is stirred at a bath temperature of 110 for 1% hours. The oil obtained after concentrating the mixture in a vacuum is taken up in absolute ethanol, and the calculated amount of gentistic acid is added. After standing for some time the crystalline bisgentisinate of the title compound is obtained. M.P. 166-168" (decomp.).

EXAMPLE 48 6-benzoyl-5,6,7,8-tetrahydro-3- l-methylhydrazino) pyrido [4,3-c1pyridazine 2.9 g. of 6-benzoyl-5,6,7,8-tetrahydro 3 methylmercaptopyrido[4,3-c1pyridazine and 1.5 g. of methylhydrazine are heated in cc. of 95 ethanol in an autoclave at a bath temperature of 150 for 18 hours, and the mixture is subsequently worked up as described in Example 47. The bisgentisinate of the title compound has a M.P. of 166-168 (decomp.).

The 6-benzoyl-5,6,7,8-tetrahydro 3 methylmercaptopyrido[4,3-c]pyridazine, used as starting material, may be obtained in a manner analogous to that described in Example 4l(b), from 34.8 g. of 6-benzoyl-5,6,7,8-tetrahydro 3 mercaptopyrido[4,3-c]pyridazine and 21.9 g. of methyl iodide. Working up is effected in a manner analogous to that described in Example 41(b), eluantzchloroform. M.P. l43-145 (decomp., from 95 ethanol).

EXAMPLE 49 3-hydrazino-5,6,7,8-tetrahydro-6- (Z) -2-methyl-2- butenoyl)pyrido [4,3-c1pyridazine A suspension of 12.6 g. of 3chloro-5,6,7,8-tetrahydro- 6-((Z)-2-methyl 2 butenoyl)pyrido[4.3-c]pyridazine in 50 cc. of hydrazine hydrate is stirred at a bath temperature of 100 for 30 minutes, and the mixture is subsequently worked up as described in Example 4. The bis- [3-hydrazino-5,6,7,8-tetrahydro-6-((Z) 2 methyl 2- butenoyl)pyrido[4,3 c]pyridazine]trisfumarate has a M.P. of 159-160 (decomp., from absolute ethanol).

The 3-chloro-5,6,7,8-tetrahydro-6-((Z) 2 methyl-2- butenoyl)pyrido[4,3 c]pyridazine, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and (Z)-2-methyl- 2-butenoyl chloride. M.P. 95-96 (decomp., from cyclohexane).

EXAMPDE 50 3-hydrazino-5,6,7,8-tetrahydro-6- (4-penten0yl) pyrido[4,3-c]pyridazine 12.3 g. of 3 -chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl) pyrido [4,3-c1pyridazine are stirred in 40 cc. of hydrazine hydrate at a bath temperature of 90 for 3 hours. The mixture is cooled with ice, 100 cc. of chloroform are added, and the excess hydrazine is separated. Upon concentrating the chloroform phase, the crude title compound is obtained as an oil. This is converted to bis[3-hydrazino- 24 5,6,7,8-tetrahydro 6 (4-pentenoyl)pyrido[4,3-c1pyridazine]trisfumarate by boiling with 4 g. of fumaric acid in 50 cc. of absolute ethanol. M.P. 132134 (decomp., from absolute ethanol).

The 3-chloro 5,6,7,8 tetrahydro- 6- (4-pentenoyl) pyrido[4,3 c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,8-tetrahydropyrido- [4.3-c]pyridazine maleate and 4-pentenoyl chloride. M.P. -92 (decomp., from carbon tetrachloride).

EXAMPLE 51 5 ,6,7,8-tetrahydro-3-( l-methylhydrazino -6- (4-pentenoyl) pyrido [4,3-c] pyridazine 12.3 g. of 3-chloro-5,6,7,8-tetrahydro-6-(4-pentenoyl) pyrido[4,3-c]pyridazine and 50 cc. of methylhydrazine are stirred at a bath temperature of 90 for 30 minutes. The crude title compound is obtained in crystalline form upon cooling the mixture with ice. The title compound has a M.P. of 128-130 (decomp., from isopropanol).

EXAMPLE 52 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c] pyridazinecarboxylic acid phenyl ester A solution of 20.3 g. of crude oily 3-chloro-5,6,7,8- tetrahydro 6 pyrido[4,3-c]pyridazinecarboxylic acid phenyl ester in 100 cc. of hydrazine hydrate is stirred in an oil bath of 100 for 1% hours. The reaction solution is concentrated in a vacuum and the residue is divided between 225 cc. of chloroform and 25 cc. of water. The crude title compound is obtained as semicrystalline residue upon concentrating the organic phase in a vacuum.

The 3-chloro 5,6,7,8 tetrahydro 6 pyrido[4,3-c] pyridazinecarboxylic acid phenyl ester, required as starting material, may be produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6, 7,8-tetrahydropyrido[4,3-e]pyridazine maleate and chloroformic acid phenyl ester. The oily crude product is used as such for the next reaction.

EXAMPLE 53 3-hydrazino-5,6,7,S-tetrahydro 8-methyl-6-pyrido[4,3-c] pyridazinecarboxylic acid ethyl ester 14.3 g. of crude 3-chloro-S,6,7,8-tetrahydro-8-methyl- 6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester are stirred in 50 cc. of hydrazine hydrate at a bath temperature of 100 for 2. /2 hours, the mixture is worked up to the crude base as described in Example 17, and this base is reacted with fumaric acid as described in Example 4. Bis(3-hydrazino 5,6,7,8 tetrahydro-8-methyl-6-pyrido- [4,3-c]pyridazinecarboxylic acid ethyl ester)trisfumarate alcoholate has a M.P. of 171-174 (decomp., from ethanol).

The starting material may be produced as follows:

(a) A mixture of 25.4 g. of 1,3-dimethyl-4-piperidone and 250 cc. of absolute benzene is added dropwise to a mixture of 65.2 g. of chloroformic acid ethyl ester in 250 cc. of absolute benzene, at room temperature, Within 30 minutes while stirring, and the reaction mixture is subsequently heated to the boil at reflux for 4 hours. The mixture is cooled with ice, a small amount of precipitated material is filtered with suction, and the filtrate is extracted thrice with 200 cc. amounts of 20% aqueous sodium chloride solution. The organic phase is concentrated in a vacuum, and the resulting 1-carbethoxy-3-methyl- 4-piperidone is purified by distillation B.P. 71-75 at 0.08 mm. of Hg..

(b) 1,2,3,6-tetrahydro 3 methyl-4-pyrro1idinylpyridine-l-carboxylic acid ethyl ester: Produced in a manner analogous to that described in Example 4(a), from 92.2 g. of l-carbethoxy-3-methyl-4-piperidone and 53.5 g. of pyrrolidine. The oily crude product is used as such for the next reaction.

(c) 1-carbethoxy-3-methyl-4-piperidone S-acetic acid ethyl ester: Produced in a manner analogous to that described in Example 4(b), from 125 g. of crude 1,2,3,6- tetrahydro-3-methyl 4-pyrrolidinylpyridine-l-carboxylic acid ethyl ester and 83.5 g. of bromoacetic acid ethyl ester. The crude product is purified by distillation. B.P. 144-149 at 0.2 mm. of Hg.

(d) 2,3,4,4a,5,6,7,8 octahydro 8 methy1-3-oxo-6- pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester: Produced in a manner analogous to that described in Example 4(0), from 27.1 g. of l-carbethoxy-3-methyl-4-piperidone- S-acetic acid ethyl ester and g. of hydrazine hydrate. M.P. 101-103 (decomp., from ether).

(e) 6-carbethoxy 5,6,7,8 tetrahydro-8-methyl-3 (2H) pyrido[4,3-c1pyridazinone: Produced in a manner analogous to that described in Example 4(d), from 15.5 g. of 2,3,4,4a,5,6,7,8 octahydro 8 methyl-3-oxo-6-pyrido[4, 3-c]pyridazine carboxylic acid ethyl ester and 10.4 g. of bromine. After cooling to room temperature, 100 g. of ice/ water are added to the mixture, the organic phase is separated and concentrated in a vacuum to an oily crude product, which crystallizes after the addition of ether. M.P. 125127 (decomp., from ether).

(f) 3-chloro 5,6,7,8 tetrahydro-8-methyl-6-pyrido- [4,3-c]pyridazinecarboxylic acid ethyl ester: Produced in a manner analogous to thatdescribed in Example 4(e), from 11.9 g. of G-carbethoxy-5,6,7,8-tetrahydro-8-methyl- 3(2H)pyrido[4,3-c]pyridazinone and 50 cc. of phosphorus oxychloride. The oily crude product is used as such for the next reaction.

' EXAMPLE 54 p 5 ,6,7,8-tetrahydro-3- l-methylhydrazino -6-pyrido- [4,3-c]pyridazinecarboxylic acid ethyl ester A solution. of 4.8 g. of 5,6,7,8-tetrahydro-3-mercapto- 6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in cc. of methylhydrazine is stirred at a bath temperature of 100 for 1 hour. The reaction solution is cooled with ice, and the precipitated reaction product is filtered off. The title compound has a M.P. of 121123 (decomp., from dimethoxyethane).

EXAMPLE 55 3-hydrazino-6-(p-phenylbenzoyl)-5,6,7,8- tetrahydropyrido [4,3-c1pyridazine 3 -hydrazino-5 ,6,7, S-tetrahydro- 6- 0-methylmercaptobenzoyl) pyrido[4,3-c] pyridazine 23.1 g. of 3-chloro-5,6,7,8-tetrahydro-6- (o-methylmercaptobenzoyl)pyrido[4,3-c]pyridazine are stirred in 100 cc. of hydrazine hydrate at a bath temperature of 100 for 2 hours, and the reaction mixture is Worked up as described in Example 17.'The gentisinate of the title compound has a M.P. of 172175.

The 3 chloro-5,6,7,8-tetrahydro-6-(o-methylmercaptobenzoyl)pyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 28.6 g. of 3-chloro- 5,6,7,8-tetral1ydropyrido[4,3-c]pyridazine maleate and 19.6. g. of o-methylmercaptobenzoyl chloride. M.P. 120- 123 (decomp., from isopropanol/ methanol).

26 EXAMPLE s7 6-benzoyl-3-cyclohexylidenehydrazin0-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine A suspension of 8.3 g. of 6-benzoyl-3-hydraZino-5,6,7,8- tetrahydropyrido[4,3-c1pyridazine in 20 cc. of cyclohexa none is boiled at reflux at a bath temperature of 180 for 2 hours. The title compound has a M.P. of 188-191 (decomp., from acetonitrile).

EXAMPLE 5 8 3-isopropylidenehydrazino-5,6,7,8-tetrahydro-6-phenacetylpyrido 4,3 -c] pyridazine 9.6 g. of crude oily 3-hydrazino-5,6,7,8-tetrahydro-6- phenacetylpyrido[4,3c]pyridazine are heated with 20 cc. of acetone on a water bath for 15 minutes. The title compound has a M.P. of 195-196 (decomp., from methanol).

The starting material may be obtained as follows:

(a) 3 chloro 5,6,7,8 tetrahydro-6-phenacetylpyrido- [4,3-c]pyridazine: Produced in a manner analogous to that described in Example 8(g), from 57.0 g. of 3-chloro- 5,6,7,8-tetrahdropyrido [4,3-c]pyridazine maleate and 46.6 g. of phenylacetic acid chloride. M.P. 156157 (decomp., from absolute ethanol).

(b) 3 hydrazine 5,6,7,8-tetrahydro-6-phenacetylpyrido[4,3-c]pyridazine: Produced in a manner analogous to that described in Example 8, from 19.5 g. of 3-chloro- 5,6,7,8 tetrahydro 6-phenacetylpyrido[4,3-c]pyridazine and 70 cc. of hydrazine hydrate with the addition of 70 cc. of isopropanol. Bath temperature reaction time 5 hours. The crude product obtained after working up is used as such for the next reaction.

EXAMPLE 59 6- (p-chlorobenzoyl -3 -isopropylidenehydrazino-S,6,7,8-

tetrahydropyrido [4,3-c] pyridazine A suspension of 3.1 g. of crude 6-(p-chlorobenzoyl)-3- hydraZino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 30 cc. of acetone is heated on a water bath for 1 hour. The title compound has a M.P. of 221223 (decomp., from ethanol).

The starting materinal may be produced as follows:

, (a) 3 chloro 6-(p-chlorobenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine: Produced in a manner analogous to that described in Example 8(g), from 3-chloro-5,6,7,-8- tetrahydropyrido[4,3-c]pyridazine maleate and p-chlorobenzoyl chloride. Reaction time 24 hours at room temperature. M.P. 172 (decomp., from absolute ethanol).

(b) 6 (p chlorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine: Produced in a manner analogous to that described in Example 8, from 15.4 g. of 3-chloro-6- (p-chlorobenzoyl -5,6,7,8-tetrahydropyrido- [4,3-c]pyridazine and 50 cc. of hydrazine hydrate with the addition of 40 cc. of dioxane. Reaction time 9 /2 hours at a bath temperature of 80, and 7 hours at room. temperature. The crystalline compound is used for the next reaction in crude state.

EXAMPLE 60 6- 3,3-diphenylpropionyl -3 -isopropylidenehydrazino- 5,6,7, 8-tetrahydropyrido [4, 3-0] pyridazine A solution of 1.5 g. of 6-(3,3-diphenypropionyl)-3-hydrazino-S,6,7,8-tetradropyrido[4,3-c]pyridazine in 40 cc. of aboslute acetone is heated on a Water bath for 35 minutes. The title compound has a M.P. of 172-175 (decomp., from absolute ethanol).

EXAMPLE 61 6- (2,4-dichlorobenzoyl) -3-isopropylidenehydrazino- 5 ,6,7, S-tetrahydropyrido [4,3-c [pyridazine A solution of 1.2 g. of crude 6(2,4-dichlorobenzoyl)-3- hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 5 cc. of acetone is heated on a Water bath for 5 minutes.

27 The title compound has a M.P. of 211214 (decomp., from methanol).

EXAMPLE 62 3-(2-butylidenehydrazino) -5,6,7,8-tetrahydro-6-myristinoylpyrido[4,3-c1pyridazine A solution of 5.2 g. of 3-hydrazino-5,6,7,8-tetrahydro-6- myristinoylpyrido[4,3-c]pyridazine in 50 cc. of methylethyl ketone is heated to the boil at reflux for 4 hours while stirring. The title compound has a M.P. 83-85 (decomp., from cyclohexane).

EXAMPLE 63 3-(3-pentylidenehydrazino) -6-pivaloyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine 1 g. of 3-hydraZino-5,6,7,8-tetrahydro-6-pivaloylpyrido- [4,3-c]pyridazine is suspended in 10 cc. of diethylketone, and heating on a water bath is effected for 1 hour. The title compound has a M.P. of 183-185 (decomp., from absolute ethanol).

EXAMPLE 64 6-butyryl-3-isopropylidenehydrazino-S,6,7,8-tetrahydropyrido [4,3-c] pyridazine A solution of 3.5 g. of crude oily 6-butyryl-3-hydrazino- 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in cc. of acetone is heated to the boil at reflux on a Water bath for 20 minutes. The title compound has a M.P. of 152-154 (decomp., from acetone).

EXAMPLE 65 3-isopropylidenehydrazino-6-octanoyl-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine A solution of 3.5 g. of crude semicrystalline 3-hydrazino 6 octanoyl-5,6,7,8-tetrahydropyrido[4,3-c]pyrida zine in 50 cc. of acetone is heated to the boil at reflux While stiriing for minutes. The title compound has a M.P. of 118-121 (decomp., from light gasoline).

EXAMPLE 66 5,6,7,8-tetrahydro-3-isopropylidenehydrazino-6-pyrido [4,3-c]pyridazinecarboxylic acid ethyl ester A suspension of 23.7 g. of 3-hydrazino-5,6,7,S-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxy1ic acid ethyl ester in 100 cc. of acetone is heated at reflux for 4 hours while stirring. The title compound has a M.P. of 171-174 (decomp., from methanol).

EXAMPLE 67 3-(Z-butylidenehydrazino)-5,6,7,8-tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid ethyl ester A suspension of 23.7 g. of 3-hyrazino-5,6,7,8-tetrahydro-6-pyrido [4,3-c]pyridazinecarboxylic acid ethyl ester in 100 cc. of methylethyl ketone is heated at reflux for 4 hours while stirring. Thhe title compound has a M.P. of 142-146 (decomp., from methanol).

EXAMPLE 68 5,6,7,8-tetrahydro-3-is0propylidenehydrazino-6-pyrido [4,3-c]pyridazinecarboxylic acid allyl ester A solution of 4 g. of 3-hydrazino-5,6,7,8-tetrahydro-6- pyrido[4,3-c]pyridazinecarboxylic acid allyl ester in cc. of acetone is heated at reflux on a water bath for 30 minutes. The title compound has a M.P. of 134-l36 (decomp).

EXAMPLE 69 3-cyclohexylidenehydrazino-5,6,7,8-tetrahydro-6- (ptoluoyl) pyrido [4,3-c] pyridazine 1.0 g. of 3-hydrazino-5,6,7,8-tetrahydro-6-(p-toluoyl) pyrido[4,3-c]pyridazine and 10 cc. of cyclohexanone are heated at reflux in an oil bath of 180 for 1 hour. The

. r, 2 p I title compound has a M.P. of 208-210 (decomp., from ethanol).

EXAMPLE 70 6-(0-fluorobenzoyl) -5,6,7,8-tetrahydro-3-isopropylidenehydrazinopyrido [4,3-c] pyridazine 1.0 g. of 6-(o-fluorobenzoyl)-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine is heated in 10 cc. of acetone on a water bath at refluxfor 30 minutes. The title compound has a M.P. of ZOO-203 (decomp., from absolute ethanol).

EXAMPLE -71 6-cyclobutanecarbonyl-3-isopropylidenehydrazino-5,6,7,8- tetrahdyropyrido [4,3-c] pyridazine A solution of 5.8 g. of 6-cyclobutanecarbonyl-3-hydraoino-S,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 50 cc. of acetone and 2 drops of glacial acetic acid is heated at reflux on a water bath for 30 minutes. The'crude product obtained as a brown oil is crystallized with absolute ethanol. The title compound has a M.P. of .175-178" (decomp., from acetone/ether).

EXAMPLE 72 6-benzoyl-3-cyclododecanylidenehydrazino-5,6,7,8-tetrahydropyrido [4,3-c] pyrid azine A suspension of 2.7 g. of 6-benzoyl-3-hydrazino-5,6,7,8- tetrahydropyrido[4,3-c]pyridazine and 1.8 g. of cyclododecanone in 20 cc. of absolute ethanol is heated on a water bath for 30 minutes, whereby a dissolution and reprecipitation clearly occurs. The resulting title compound is recrystallized from a mixture of 160 cc. of methanol and 30 c. of dimethyl formamide. M.P. 222-225 (decomp).

EXAMPLE 73 3-(2-butylidenehydrazino)-6-(p-phenylbenzoyl)-5,6,7,8- tetrahydropyrido [4,3-c]pyridazine 0.5 g. of 3hydrazino-6-(p-phenylbenzoyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine are heated in 5 cc. of methylethyl ketone on a water bath for 1 hour. The title compound has a M.P. of 260-262 (decomp., from methylethyl ketone).

EXAMPLE 74 5,6,7,8-tetrahydro-3-isopropylidenehydrazino-8-methyl-6- pyrido[4,3-c1pyridazinecarboxylic acid ethyl ester A solution of 1 g. of bis(3-hydrazino-5,6,7,8-tetrahydro- 8-methyl 6 pyrido[4,3-c]pyridazine)trisfumarate alcoholate in 10 cc. of acetone is heated on a water bath for 15 minutes. The reaction mixture is cooled with ice, and the title compound which crystallizes is divided between cc. of chloroform and 5 cc. of concentratedaqueous ammonia solution, the chloroform phase is separated and concentrated. The title compoundhas a M.P. of -142 (decomp., from absolute ethanol).

EXAMPLE 75 5 ,6,7,8,9,10, l 1,12,13, 14-decahydro-3-isopropylidenehy drazinocyclododeca [c] pyridazine 29 EXAMPLE 76 ,6,7,8,9, 1 O-hexahydro-3-isopropylidenehydrazinocycloocta [c] pyridazine A solution of 0.5 g. of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 15 cc. of absolute acetone is heated on a water bath for 1 hour. After cooling the title compound crystallizes. M.P. 165-167" (decomp.).

EXAMPLE 77 3-cyclohexylidenehydrazino-5,6,7,8,9,10-hexahydrocycloocta [c] pyrid azine A solution of 10.0 g. of 3-hydrazino-5,6,7,8,9,lO-hexahydrocycloocta[c]pyridazine in 100 cc. of cyclohexanone is boiled at reflux at a bath temperature of 180 for 1 hour and 45 minutes. The mixture is concentrated in a vacuum, whereby the crystalline title compound is obtained and is recrystallized from isopropanol. M.P. 160 162 (decomp.).

EXAMPLE 78 6-benzoyl-3-isopropylidenehydrazino-5,6,7,S-tetrahydropyrido [4,3-c1pyridazine A solution of 0.5 g. of 6-benzoyl-3-hydrazino-5,6,7,8- tetrahydropyrido[4,3-c]pyridazine in 15 cc. of absolute acetone, to which 4 drops of glacial acetic acid have been added, is heated on a water bath for 1 hour. The solution is concentrated in a vacuum, and the crude title compound, obtained as an oil, is crystallized with ether. The title compound has a M.P. of 188190 (decomp.).

EXAMPLE 79 6-benzoy1-3-(Z-butylidenehydrazino)-5,6,7,8-tetrahydropyrido [4,3 -c] pyridazine A suspension of 13.5 g. of 6 benzoyl-3-hydrazino- 5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 100 cc. of methylethyl ketone is heated at reflux While stirring for 4 hours. The title compound has a M.P. of 191-193, from 95% ethanol.

EXAMPLE 80 3-hydrazino-5,6,7,8,9,IO-hexahydrocycloocta[c]- pyridazine A solution of 10.1 g. of 3-mercapto-5,6,7,8,9,IO-hexahydrocycloocta[c]pyridazine in 75 cc. of hydrazine hydrate and 50 cc. of dioxane is heated at a bath temperature of 110 while stirring for 24 hours. Upon cooling the reaction mixture, the title compound precipitates and is purified by washing with a small amount of water and recrystallizing from 95% ethanol. The title compound has a M.P. of 145148 (decomp., from absolute ethanol).

The starting material may be produced as follows:

59.1 g. of 3chloro-5,6,7,8,9,10-hexahydrocycloocta[c]- pyridazine and 25.2 g. of thiourea are heated at reflux in 250 cc. of absolute ethanol while stirring for 20 hours. The reaction mixture is subsequently concentrated and divided between chloroform and water. After concentrating the chloroform phase, crude 3-mercapto-5,6,7,8,9,l0- hexahydrocycloocta[c]pyridazine is obtained and is recrystallized from 250 cc. of absolute ethanol with the addition of carbon. M.P. 167-170 (decomp.).

What is claimed is:

1. A compound of the formula:

wherein R is amino, or

wherein each of R and R is alkyl of 1 to 4 carbon atoms, or R and R together with the carbon to which they are bound, form cycloalkylidene having 5 to 12 carbon atoms,

R is hydrogen or methyl,

R is alkyl of 1 to 16 carbon atoms, alkenyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, l-adamantyl, or -(CH R wherein m is 0 or an integer from 1 to 4, and

R is phenyl; phenyl monosubstituted by fluorine, chlorine, bromine, alkyl or alkoxy of 1 to 4 carbon atoms, alkylmercapto of 1 to 4 carbon atoms, or phenyl; phenyl substituted by two or three substituents selected from the group consisting of chlorine, alkyl or alkoxy of 1 to 4 carbon atoms; diphenylmethyl, the phenyl rings of which may be monosubstituted by fluorine, chlorie, bromine, alkyl or alkoxy of 1 to 4 carbon atoms; or naphthyl,

or -OR wherein R is alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or phenyl or phenylalkyl which may be monosubstituted on the phenyl ring by chlorine; alkyl or alkoxy of 1 to 4 carbon atoms, and in which the alkylene chain of phenylalkyl is of 1 to 4 carbon atoms, and

R and R are each hydrogen or alkyl of 1 to 4 carbon atoms, provided that when R is phenyl substituted with more than one tertiary butyl or tertiary butoxy, they are on other than adjacent carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of Claim 1, which is 6-benzoyl-3- hydrazino-5,6,7,8-tetrahydropyrido [4,3-c] pyridazine.

3. The compound of Claim 1, which is 3-hydrazino-5,6,- 7,8-tetrahydro-6-(0-to1uoyl)pyrido [4,3-c]pyridazine.

4. The compound of Claim 1, which is 6-benzoy1-5,6,- 7,8 tetrahydro-3-(l-methylhydrazino) pyrido[4,3-c]pyridazine.

5. The compound of Claim 1, which is 6-(0-chlorobenoyl) 3 -hydrazino-5,6,7,8-tetrahydropyrido[4,3-c1pyridazine.

6. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro-6-(3 phenylpropionyl)pyridol[4,3-c] pyridazine.

7. The compound of Claim 1, which is 6-(p-tert.butylbenzoyl) -3-hydrazino-5,6,7,8 tetrahydropyrido [4,3-c1pyridazine.

8. The compound of Claim 1, which is 6-(3,3-dipheny1- propionyl) 3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c] pyridazine.

9. The compound of Claim 1, which is 6-(3,4-dichlorobenzoyl) 3-hydrazino-5,6,7,8 tetrahydropyrido[4,3-c] pyridazine. l 1

10. The compound of Claim 1, which is 6-(2,6-dichlorobenzoyl) 3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c] pyridazine.

11. The compound of Claim 1, which is 6-(2,3-dimethylbenzoyl)-3 hydrazino-5, 6,-7,8-tetrahydropyrido[4,3-c] pyridazine. 1

12. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro 6 (3,4,5-trimethoxybenzoyl)pyrido- [4,3-c] pyridazine.

13. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro-6 (4 pheny1butyryl)pyrido[4,3-c] pyridazine.

14. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro-6-(p to1uoyl)pyrido[4,3-c] pyridazine.

15. The compound of Claim 1, which is 6-(m-chlorobenzoyl)-3 hydrazino-5,6,7,8 tetrahydropyrido[4,3-c] pyridazine.

16. The compound of Claim 1, which is 6-(p-bromobenzoyl)-3 hydrazino-5,6,7,8 tetrahydropyrido[4,3-c] pyridazine.

17. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro 6 (p-methoxybenzoyl)pyrido[4,3-c] pyridazine.

18. The compound of Claim 1, which is 6-(o-fluorobenzoyl) B-hydrazino 5,6,7,8-tetrahydropyrido[4,3-c] pyridazine.

19. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8 tetrahydro-6-(o-methylphenacetyl)pyrido[4,3-c] pyridazine.

20. The compound of Claim 1, which is 6-(p -ethoxybenzoyl) 3-hydrazino 5,6,7,8-tetrahydropyrido[4,3-c] pyridazine.

21. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro -6-(2 naphthoyl)pyrido [4,3-c]pyridazme.

22. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8 tetrahydro-6-pivaloylpyrido[4,3c]pyridazine.

23. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8 tetrahydro-6-myristinoylpyrido[4,3-c]pyridazine.

24. The compound of Claim 1, which is 6-butyryl-3- hydrazino-5,6,7,8 tetrahydropyrido[4,3-c]pyridazine.

25. The compound of Claim 1, which is S-hydrazino- 6-octanoyl 5,6,7,8-tetrahydropyrido [4,3-c]pyridazine.

26. The compound of Claim 1, which is 3-hydrazino 5,6,7,8 tetrahydro 6-(2-n-propylvaleroyl)pyrido [4,3-c] pyridazine.

27. The compound of Claim 1, which is 3-hydrazino- 6-hexahydrobenzoyl 5,6,7,8 tetrahydropyrido[4,3-c] pyridazine.

28. The compound of Claim 1, which is 6-(1-adamantonyl)-3-hydrazino 5,6,7,8 tetrahydropyrido[4,3-c] pyridazine.

29. The compound of Claim 1, which is fi-cyclobutanecarbonyl-3-hydrazino 5,6,7,8 tetrahydropyrido[4,3-c] pyridazine.

30. The compound of Claim 1, which is S-hydrazino- 5,6,7,8-tetrahydro 6-pyrido [4,3-c]pyridazinccarboxylic acid ethyl ester.

31. The compound of Claim 1, which is 5,6,7,8-tetrahydro-3-(1-methylhydrazino) 6-pyrido [4,3-c]pyridazinecarboxylic acid ethyl ester.

32. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro 6 pyrido[4,3-c]pyridazinecarboxylic acid methyl ester.

33. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro 6-py1'id0[4,3-c]pyridazinecarboxylic acid benzyl ester.

34. The compound of Claim 1, which is S-hydrazino- 5,6,7,8 tetrahydro-6 pyrido [4,3-c]pyridazinecarboxylic acid allyl ester.

35. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8 tetrahydro 6-((Z)-2-methyl-2-butenoyl)pyrido [4,3-c]pyridazine.

36. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8 tetrahydro 6-(4-pentenoyl)pyrido[4,3-c]pyridazme.

37. The compound of Claim 1, which is 5,6,7,8-tetra hydro-3-(1 methylhydrazino) 6-(4-pentenoyl)pyrido [4,3-c]pyridazine.

38. The compound of Claim 1, which is B-hydrazino- 5,6,7,8-tetrahydro 6 pyrido[4,3-c]pyridazinecarboxylic acid phenyl ester.

39. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro 8 methyl-6-pyrido[4,3-c1pyridazinecarboxylic acid ethyl ester.

40. The compound of Claim 1, which is 3-hydrazino- 6-(p-phenylbenzoyl) 5,6,7,8 tetrahydropyrido[4,3 c] pyridazine.

41. The compound of Claim 1, which is 3-hydrazino- 5,6,7,8-tetrahydro 6 (o-methylmercaptobenzoyl)pyrido- [4,3-c]pyridazine.

42. The compound of Claim 1, which is 6-benzoyl-3- cyclohexylidenehydrazino 5,6,7,8 tetrahydropyrido[4,3- c] pyridazine.

43. The compound of Claim 1, which is 3-isopropylidenehydrazino-5,6,7,8-tetrahydro 6 phenacetylpyrido- [4,3-c]pyridazine.

44. The compound of Claim 1, which is 6-(p-chlorobenzoyl) 3 isopropylidenehydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine.

45. The compound of Claim 1, which is 6-(3,3-diphenylpropionyl) 3 isopropylidenehydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine.

46. The compound of Claim 1, which is 6-(2,4-dichlorobenzoyl) 3 isopropylidenehydrazino-S,6,7,8-tetrahydropyrido[4,3-c1pyridazine.

47. The compound of Claim 1, which is 3-(2-butylidenehydrazino)-5,6,7,8-tetrahydro 6 myristinoylpyrido- [4,3-c]pyridazine.

48. The compound of Claim 1, which is 3-(3-pentylidenehydrazino) 6 pivaloyl 5,6,7,8 tetrahydropyrido- [4,3-c]pyridazine.

49. The compound of Claim 1, which is 6-butyryl-3- isopropylidenehydrazino 5,6,7,8 tetrahydropyrido[4,3- c] pyridazine.

50. The compound of Claim 1, which is 3-isopropylidenehydrazino 6 octanoyl-5,6,7,8-tetrahydropyrido[4,3- c] pyridazine.

51. The compound of Claim 1, which is 5,6,7,8-tetrahydro 3 isopropylidenehydrazino-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester.

52. The compound of Claim 1, which is 3-(2-butylidenehydrazino)-5,6,7,8-tetrahydro 6 pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester.

53. The compound of Claim 1, which is 5,6,7,8-tetrahydro 3 isopropylidenehydrazino-6-pyrido [4,3-c]pyridazinecarboxylic acid allyl ester.

54. The compound of Claim 1, which is 3-cyclohexylidenehydrazino-S,6,7,8-tetrahydro 6 (p-toluoyl)pyrido- [4,3-c]pyridazine.

55. The compound of Claim 1, which is 6-(o-fluorobenzoyl)-5,6,7,8-tetrahydro 3 isopropylidenehydrazinopyrido[4,3-c]pyridazine.

56. The compound of Claim 1, which is 6-cyclobutanecarbonyl 3 isopropylidenehydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine.

57. The compound of Claim 1, which is 6-benzoyl-3- cyclododecanylidenehydrazino 5,6,7,8-tetrahydropyrido- [4,3-cjlpyridazine.

58. The compound of Claim 1, which is 3-(2-butylidenehydrazino) 6 (p-phenylbenzoyl)-5,6,7,8 tetrahydropyrido [4,3-c1pyridazine.

59. The compound of Claim 1, which is 5,6,7,8-tetrahydro 3 isopropylidenehydrazino 8 methyl-6-pyrido- [4,3-c]pyridazinecarboxylic acid ethyl ester.

60. The compound of Claim 1, which is 6-benzoyl-3- isopropylidenehydrazino 5,6,7,8 tetrahydropyrido[4,3- c]pyridazine.

61. The compound of Claim 1, which is 6-benzoyl-3- (2-butylidenehydrazino) 5,6,7,8 tetrahydropyrido[4,3- c]pyridazine.

62. The compound of Claim 1, which is S-hydrazino- 5,6,7,8-tetrahydro-6-phenacetylpyrido[4,3-c]pyridazine.

63. The compound of Claim 1, which is 3-hydrazino- 6-(p-chlorobenzoyl) 5,6,7,8 tetrahydropyrido[4,3-c]pyridazine.

(References on following page) 33 34 References Cited DONALD G. DAUS, Primary Examiner UNITED STATES PATENTS R. D. MCCLOUD, Assistant Examiner 3,205,230 9/1965 Prlbyl et a1. 260-25O A Us. CL X'R- OTHER REFERENCES Daunis et al.: Chemical Abstract 75 :129731s (1971) and 1967-71 Chemical Abstracts Subject Index, p. 7505s. Sprio et 211.: Chemical Abstract, 75 :110259x (1971).

5 260240 R, 250 C, 250 AC, 326.8, 326.81, 293.76, 295 

